5-cyano-4- (pyrrolo [2,3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

CROSS-REFERENCE

This application is a divisional application of U.S. application Ser.No. 13/477,663, filed on May 22, 2012 which claims priority to: U.S.application Ser. No. 12/448,489, filed on Jun. 22, 2009; PCT ApplicationNo. PCT/US2007/026190, filed Dec. 21, 2007; U.S. Application No.60/876,307, filed on Dec. 21, 2006; U.S. Application No. 60/922,291,filed on Apr. 6, 2007; U.S. Application No. 60/947,707, filed on Jul. 3,2007; and U.S. Application No. 60/989,014, filed on Nov. 19, 2007. Theentire contents of these applications are incorporated herein byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders. Theinvention also provides processes for preparing the compounds of theinvention.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of intensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell (see Hardie, G. et al., TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.:1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids etc). Sequence motifs have beenidentified that generally correspond to each of these kinase families(see, e.g., Hanks, S. K., Hunter, T., FASEB J., 1995, 9, 576-596;Knighton et al., Science, 1991, 253, 407-414; Hiles et al, Cell, 1992,70, 419-429; Kunz et al, Cell, 1993, 73, 585-596; Garcia-Bustos et. al.,EMBO J., 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor alpha (TNF-a), and growth factors (e.g.,granulocyte macrophage-colony stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, survival and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, cancer, autoimmune diseases,inflammatory diseases, bone diseases, metabolic diseases, neurologicaland neurodegenerative diseases, cardiovascular diseases, allergies andasthma, Alzheimer's disease and hormone related diseases. Accordingly,there has been a substantial effort in medicinal chemistry to findprotein kinase inhibitors that are effective as therapeutic agents.

The Polo-like kinases (PLK) belong to a family of serine/threoninekinases that are highly conserved across the species, ranging from yeastto man (reviewed in Lowery, D. M. et al., Oncogene, 2005, 24; 248-259).The PLK kinases have multiple roles in cell cycle, including control ofentry into and progression through mitosis.

PLK1 is the best characterized of the PLK family members. PLK1 is widelyexpressed and is most abundant in tissues with a high mitotic index.Protein levels of PLK1 rise and peak in mitosis (Hamanaka, R. et al., J.Biol. Chem., 1995, 270, 21086-21091). The reported substrates of PLK1are all molecules that are known to regulate entry and progressionthrough mitosis, and include CDC25C, cyclin B, p53, APC, BRCA2 and theproteasome. PLK1 is upregulated in multiple cancer types and theexpression levels correlate with severity of disease (Macmillan, J C etal., Ann. Surg. Oncol., 2001, 8, 729-740). PLK1 is an oncogene and cantransform NIH-3T3 cells (Smith, M. R. et al., Biochem. Biophys. Res.Commun., 1997, 234, 397-405). Depletion or inhibition of PLK1 by siRNA,antisense, microinjection of antibodies, or transfection of a dominantnegative construct of PLK1 into cells, reduces proliferation andviability of tumour cells in vitro (Guan, R. et al., Cancer Res., 2005,65, 2698-2704; Liu, X. et al., Proc. Nat'l. Acad. Sci. USA, 2003, 100,5789-5794; Fan, Y. et al., World J. Gastroenterol., 2005, 11, 4596-4599;Lane, H. A. et al., J. Cell Biol 1996, 135, 1701-1713; Wada, M. et al.,Biochem. Biophys. Res. Commun., 2007, 357(2): 353-359; Rizki, A. et al.,Cancer Res., 2007, 67 (23): 11106-11100). Tumour cells that have beendepleted of PLK1 have activated spindle checkpoints and defects inspindle formation, chromosome alignment and separation and cytokinesis.Loss in viability has been reported to be the result of an induction ofapoptosis. In contrast, normal cells have been reported to maintainviability on depletion of PLK1. In vivo knock down of PLK1 by siRNA orthe use of dominant negative constructs leads to growth inhibition orregression of tumours in xenograft models.

PLK2 is mainly expressed during the G1 phase of the cell cycle and islocalized to the centrosome in interphase cells. PLK2 knockout micedevelop normally, are fertile and have normal survival rates, but arearound 20% smaller than wild type mice. Cells from knockout animalsprogress through the cell cycle more slowly than in normal mice (Ma, S.et al., Mol. Cell. Biol., 2003, 23, 6936-6943). Depletion of PLK2 bysiRNA or transfection of kinase inactive mutants into cells blockscentriole duplication. Downregulation of PLK2 also sensitizes tumourcells to taxol and promotes mitotic catastrophe, in part by suppressionof the p53 response (Burns, T. F. et al., Mol. Cell. Biol., 2003, 23,5556-5571).

PLK3 is expressed throughout the cell cycle and increases from G1 tomitosis. Expression is upregulated in highly proliferating ovariantumours and breast cancer and is associated with a worse prognosis(Weichert, W. et al., Br. J. Cancer, 2004, 90, 815-821; Weichert, W etal., Virchows. Arch., 2005, 446, 442-450). In addition to regulation ofmitosis, PLK3 is believed to be involved in Golgi fragmentation duringthe cell cycle and in the DNA-damage response Inhibition of PLK3 bydominant negative expression is reported to promote p53-independentapoptosis after DNA damage and suppresses colony formation by tumourcells (Li, Z. et. al., J. Biol. Chem., 2005, 280, 16843-16850).

PLK4 is structurally more diverse from the other PLK family members.Depletion of this kinase causes apoptosis in cancer cells (Li, J. et.al., Neoplasia, 2005, 7, 312-323). PLK4 knockout mice arrest at E7.5with a high fraction of cells in mitosis and partly segregatedchromosomes (Hudson, J. W. et. al., Current Biology, 2001, 11, 441-446).

Molecules of the protein kinase family have been implicated in tumourcell growth, proliferation and survival. Accordingly, there is a greatneed to develop compounds useful as inhibitors of protein kinases. Theevidence implicating the PLK kinases as essential for cell division isstrong. Blockade of the cell cycle is a clinically validated approach toinhibiting tumour cell proliferation and viability. It would thereforebe desirable to develop compounds that are useful as inhibitors of thePLK family of protein kinases (e.g., PLK1, PLK2, PLK3 and PLK4), thatwould inhibit proliferation and reduce viability of tumour cells,particularly as there is a strong medical need to develop new treatmentsfor cancer.

SUMMARY OF THE INVENTION

Compounds of this invention are useful as inhibitors of PLK proteinkinases and in some embodiments, as inhibitors of PLK1 protein kinases.These compounds are as defined herein.

These compounds, and pharmaceutically acceptable salts thereof, areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, an autoimmune, inflammatory,proliferative, or hyperproliferative disease, a neurodegenerativedisease, or an immunologically-mediated disease. The compounds providedby this invention (and pharmaceutically acceptable salts andpharmaceutically acceptable derivatives thereof) are also useful for thestudy of kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION Compounds of the Invention

This invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein:

-   -   R¹ is —H, halogen, C₁₋₆ aliphatic optionally substituted with        1-3 R³, —O(C₁₋₆ aliphatic) optionally substituted with 1-3 R³,        or —N(H)R;    -   Each R is independently H, C₁₋₆ aliphatic, aryl, heteroaryl,        C₃₋₈ cycloalkyl, or 4-12 membered heterocyclic ring optionally        containing 1-3 groups selected from —N(R¹⁷)—, —O—, or —S—;        wherein each of the aliphatic, aryl, heteroaryl, cycloalkyl, and        heterocyclic ring are optionally substituted with 1-3 of Q;    -   Each Q is independently selected from halogen, hydroxy, C₁₋₆        alkyl, benzyl, oxo, —CF₃, W, —CN, —NH₂, —N(H)—W, —N(W)₂,        —N(H)—SO₂—W, —S(O)₂—N(H)—W, —S(O)₂—N(W)₂, —C(O)—W, —C(O)—N(W)₂,        —N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, —SO₂—W, SW or —OW;    -   Two Q can be linked together to form a 4- to 8-membered        carbocyclic or heterocyclic ring optionally substituted with        C₁₋₃ alkyl or CF₃;    -   Each W is independently selected from —H, C₁₋₆ alkyl, aralkyl,        cycloalkyl or heterocyclic ring; each C₁₋₆ alkyl, aralkyl,        cycloalkyl or heterocyclic ring is optionally substituted with        1-3 of halogen, —OR⁶, —CN, C₁₋₆ alkyl or NR¹⁸R¹⁹; or    -   One W, together with the nitrogen atom to which it is attached        and a carbon atom of R, form a 4- to 8-membered ring; or    -   Two W, together with the same or different nitrogen atom or        carbon atom to which they are attached, form a 4- to 8-membered        heterocyclic ring;    -   Each R¹⁸ and R¹⁹ is independently hydrogen or C₁₋₃ alkyl; or    -   R¹⁸ and R¹⁹, together with the nitrogen atom to which they are        attached, form a 4- to 8-memebered heterocyclic ring, optionally        substituted with C₁₋₃ alkyl or CF₃;    -   Two W can be linked together to form a 4- to 8-membered        cycloalkyl or heterocycloalkyl optionally substituted with C₁₋₃        alkyl or CF₃;    -   R² is —NR⁴R⁵, —OR⁶, —SR⁶, or —NR¹⁰R¹¹;    -   Each R³ is independently halogen, C₁₋₆ alkyl, aryl, or        heteroaryl;    -   Each R⁴ is independently —H or C₁₋₆ aliphatic optionally        substituted with 1-3 R⁷;    -   Each R⁵ is independently C₁₋₆ aliphatic optionally substituted        with 1-4 R⁷ or a 4- to 8-membered monocyclic or 6- to        10-membered bicyclic ring optionally substituted with 1-4 R², or    -   R⁴ and R⁵ can be joined together to form a monocyclic or        bicyclic ring optionally substituted with 1-3 R⁹;    -   Each R⁶ is independently H, C₁₋₆ alkyl, -L-aryl, or        -L-heteroaryl, wherein each of the C₁₋₆ alkyl, -L-aryl, or        -L-heteroaryl is optionally and independently substituted with        1-3 R⁸;    -   L is C₀₋₃ alkyl;    -   Each R⁷ is independently oxo, alkyl, halogen, —CN, —OR⁹, —SR⁹,        —N(R⁹)₂, C₃₋₈ cycloalkyl, aryl, heteroaryl or a 4- to 8-membered        heterocyclic ring containing 1-3 groups selected from —N(R¹⁷)—,        —O—, or —S—, wherein each alkyl, cycloalkyl, 4-8 membered        heterocyclic monocyclic or bicyclic ring, aryl, and heteroaryl        is optionally and independently substituted with 1-3 R⁸, or    -   Two R⁷ on the same atom or adjacent atoms is joined to form a        carbocyclic ring or a 4-8 membered heterocyclic ring containing        1-3 groups selected from —N(R¹⁷)—, —O—, or —S—, wherein each of        the carbocyclic ring and the 4- to 8-membered heterocyclic ring        is optionally and independently substituted with 1-3 R⁸;    -   Each R⁸ is independently —R, -Q, —R⁹, —OR⁹, —N(R⁹)₂, halogen, or        —CN;    -   Each R⁹ is independently —H, —N(R¹⁶)₂, C₃₋₆ carbocyclic ring,        C₃₋₆ heterocyclic ring, or Cl_(—)3 aliphatic, wherein C₃₋₆        carbocyclic ring, C₃₋₆ heterocyclic ring and C₁₋₃ aliphatic are        each optionally substituted with 1-3 Q; or    -   Two R⁹ groups together with the N atom to which they are bound        form a 4-8 membered ring additionally containing 1 or 2 groups        each indpednetly selected from —N(R¹⁷)—, —O—, or —S—, wherein        the 4- to 8-membered ring is optionally and independently        substituted with 1-3 of W;    -   Each R¹⁶ is independently hydrogen or C₁₋₆ alkyl, or    -   Two R¹⁶ groups together with the N atom to which they are bound        form a 4- to 8-membered ring containing 1 or 2 groups selected        from NR¹⁷, O, or S;    -   Each R¹⁷ is independently, hydrogen, Q₁ or C₁₋₄ aliphatic or        cycloaliphatic, wherein each C₁₋₄ aliphatic or cycloaliphatic is        optionally substituted with 1-3 of Q;    -   Q₁ is Cl_(—)6 alkyl, benzyl, —S(O)₂—N(H)—W, —S(O)₂—N(W)₂,        —C(O)—W, —C(O)—N(W)₂, —C(O)—N(H)—W, —N(H)—C(O)—W, —O—C(O)—W,        —C(O)—O—W, or —SO₂—W;    -   R¹⁰ is —H or C₁-C₆ aliphatic optionally substituted with 1-3 R⁷;    -   R¹¹ is —C(R¹²R¹³)C(═O)NR¹⁴R¹⁵;    -   Each of R¹² and R¹³ is independently H or C₁₋₆ aliphatic        optionally substituted with 1-3 R⁷; or    -   R¹² and R¹³ can be joined together to form a ring optionally        substituted with 1-3 R⁹; or    -   R¹⁰ and R¹² can be joined together to form a ring optionally        substituted with 1-3 R⁹; and    -   Each R¹⁴ and R¹⁵ is independently H, C₁₋₆ alkyl, carbocyclic, or        heterocyclic optionally substituted with 1-3 R⁷; or    -   R¹⁴ and R¹⁵ can be joined together to form a ring optionally        substituted with 1-3 R⁹.

In some embodiments, R⁴ is H or C₁₋₄ alkyl and R⁵ is selected from —CH₃,

In some embodiments, R⁴ is H or C₁₋₄ alkyl and R⁵ is a hydroxyalkyl,hydroxcycloalkyl or alkoxyalkyl selected from

In some embodiments, R⁴ is H or C₁₋₄ alkyl and R⁵ is a substituted alkylselected from

In some embodiments, R⁴ is H or C₁₋₄ alkyl, and R⁵ is an aryl or aralkylselected from

In some embodiments, R⁴ is H or C₁₋₄ alkyl and R⁵ is an optionallysubstituted heteroaralkyl selected from

In some embodiments, R⁴ is H and R⁵ is an optionally substituted aralkylor heteroaralkyl, which give compounds of formula Ic

wherein each X is independently CR⁸ or N and K is −OR⁶, —SR⁶, or—N(R⁹)₂.

In some embodiments, R⁴ is H or C₁₋₄ alkyl and R⁵ is a cycloalkyl orcycloalkyl(alkyl), each optionally substituted, and selected from

In other embodiments, R⁴ is H and R⁵ is an amino substitutedcycloalkyl(alkyl), which give the compounds of formula Ib

In other embodiments, R⁴ is H or C₁₋₄ alkyl, and R⁵ is aheterocycloalkyl or heterocycloalkyl(alkyl), each optionallysubstituted, and selected from

In some embodiments, R⁴ is H and R⁵ is a heterocycloalkyl(alkyl), whichgive the compounds of formula Ia

wherein

represents a 4- to 8-membered nitrogen containing heterocyclic ring.

In one embodiment, R⁴ and R⁵ are joined together to form

In other embodiments, R² is —NR¹⁰R¹¹ wherein R¹⁰ is H and R¹¹ isselected from

In another embodiment, R² is —SR⁶ wherein R⁶ is selected from CH₃—,

In some embodiments, the compounds of this invention have one of more ofthe following features: R⁷ is a 4- to 10-membered heterocyclicmonocyclic or bicyclic ring optionally substituted with 1-3 of R⁸; R⁷ isa 4- to 6-membered heterocyclic monocyclic ring optionally substitutedwith 1-3 of R⁸; R⁸ is Q; Q is selected from —C(O)—W, —C(O)—N(W)₂,—C(O)—O—W, or —SO₂—W; Q is —C(O)—W.

In some embodiments, the compounds of this invention have one of more ofthe following features: R⁷ is a C₃-C₈ carbocycle optionally substitutedwith 1-3 R⁸; one R⁸ is Q; Q is selected from hydroxy, —NH₂, —N(H)—W,|—N(W)₂, —N(H)—SO₂—W, —C(O)—N(W)₂, —N(H)—C(O)—W, or —O—C(O)—W; Q is—N(H)—C(O)—W.

In some embodiments, the compounds of this invention have one of more ofthe following features: R¹ is halogen (e.g., —Cl); R¹ is C₁₋₆ aliphatic(e.g., alkyl, alkenyl, or alkynyl) optionally substituted with 1-3 ofR³, and each R³ is independently halo, aryl, or heteroaryl; R¹ is methyloptionally substituted with 1-3 R³ and each R³ is independently halo; R¹is —CF₃; R¹ is —CH₃; R¹ is —NHR and R is H, C₁₋₆ aliphatic (e.g.,alkyl), aryl, or C₃₋₈ cycloalkyl.

In some embodiments, the compounds of this invention have one or more ofthe following features: R² is —NR⁴R⁵ or —NR¹⁰R¹¹; R² is —NR⁴R⁵, Kwherein R⁴ is H or C₁₋₆ aliphatic optionally substituted with 1-3 R⁷,and R⁵ is C₁₋₆ aliphatic optionally substituted with 1-4 R⁷ or a 3- to6-membered monocyclic or 6- to 10-membered bicyclic ring optionallysubstituted with 1-4 R⁷; R⁴ is H or C₁₋₆ aliphatic, and R⁵ is C₁₋₆ alkylthat is optionally substituted with 1-4 of R⁷; R⁴ is H, and R⁵ is C₁₋₄alkyl and optionally substituted with 1-4 R⁷; R⁵ is ethyl substituted atthe carbon atom attached to the nitrogen atom with R⁷; R⁷ is an aryl orheteroaryl, and is optionally substituted with 1-3 of R⁸; R⁷ is phenyl,pyridyl, or pyrimidyl, and is optionally substituted with 1-3 of R⁸; R⁷is phenyl optionally substituted with 1-3 of R⁸; R⁷ is phenyl optionallysubstituted at the ortho- or meta-position with R⁸ and also optionallysubstituted at the para-position with R⁸ (e.g., the optional substituentR⁸ at an ortho- or meta-position, when present, is halo).

In some embodiments of the compounds of this invention,

-   -   R⁷ is phenyl substituted at the para-position with —R or        —N(R⁹)₂;    -   R is 4- to 8-membered heterocyclic ring optionally containing        1-3 groups each independently selected from —N(R¹⁷)—, —O—, or        —S—, and the heterocyclic ring is optionally substituted with        1-3 of Q;    -   Each Q is independently selected from halogen, hydroxy, C₁₋₆        alkyl, benzyl, —CF₃, W, —C(O)—W, —C(O)—N(W)₂, —C(O)—O—W;    -   Each W is independently selected from —H, C₁₋₆ alkyl, or        cycloalkyl;    -   Each R⁹ is independently —H, C₃₋₆ heterocyclic ring, or C₁₋₃        aliphatic, wherein C₃₋₆ heterocyclic ring and C₁₋₃ aliphatic are        each optionally substituted with 1-3 Q; or    -   Two R⁹ groups together with the N atom to which they are bound        form a 4- to 8-membered ring containing additional 1 or 2 groups        each independently selected from —N(R¹⁷)—, —O—, or —S—, wherein        the 4- to 8-membered ring is optionally and independently        substituted with 1-3 of W.

In still some embodiments of the compounds of this invention, R⁷ isoptionally substituted at an ortho-position with fluoride.

In some embodiments, the compounds of this inventions have the followingfeatures:

-   -   R is 5- to 7-membered heterocyclic ring optionally containing 2        nitrogen atoms and optionally substituted with 1-3 of Q;    -   Each R⁹ is independently —H, C₃₋₆ heterocyclic ring, or C₁₋₃        aliphatic, wherein C₃₋₆ heterocyclic ring and C₁-C₃ aliphatic        are each optionally substituted with 1-3 Q; or    -   Two R⁹ groups together with the N atom to which they are bound        form a 6- to 7-membered ring containing an additional nitrogen        atom and optionally substituted with 1-3 of W.

Still some of the compounds of this invention have one or more of thefollowing features: R is piperazine optionally substituted with 1-3 ofQ; R⁷ is

R⁷ is phenyl substituted at the para-position with —OR⁹; R⁹ is —H, C₃₋₆heterocycloalkyl ring, or C₁₋₃ alkyl, wherein C₃₋₆ heterocycloalkyl ringand C₁₋₃ alkyl are each optionally substituted with 1-3 Q; R⁹ ispyrrolidinyl or piperidinyl and optionally substituted with 1-3 Q; R⁹ is

Still some of the compounds of this invention have one or more of thefollowing features: R⁷ is pyrimidinyl optionally substituted with 1-3 ofR⁸; R⁷ is 5-pyrimidyl optionally substituted at the 2-position with R⁸;R⁸ is —R⁹, —OR⁹, —SR⁹, —N(R⁹)₂, halogen, or —CN; Each R⁹ isindependently —H, C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclic ring, or C₁₋₃aliphatic, wherein C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclic ring andC₁₋₃ aliphatic are each optionally substituted with 1-3 Q; R⁷ is

R⁷ is pyridinyl optionally substituted with 1-3 of R⁸; R⁷ is 3-pyridinyloptionally substituted with 1-3 of R⁸; R⁷ is 3-pyridinyl optionallysubstituted at the 6-position with R⁸; R⁸ is -Q, —R⁹, —OR⁹, —N(R⁹)₂,halogen, or —CN; each R⁹ is independently —H, C₃₋₆ heterocyclic ring, orC₁₋₃ aliphatic, wherein C₃₋₆ heterocyclic ring and C₁₋₃ aliphatic areeach optionally substituted with 1-3 Q; or two R⁹ groups together withthe N atom to which they are bound form a 4- to 8-memberedheterocycloalkyl ring optioanlly containing an additional 1 or 2 groupsselected from —N(R¹⁷)—, —O—, or —S—, wherein the 4- to 8-memberedheterocycloalkyl ring is optionally and independently substituted with1-3 of W; each R¹⁷ is independently, hydrogen, or C₁₋₄ aliphatic,wherein each C₁₋₄ aliphatic is optionally substituted with 1-3 of Q;each Q is independently selected from halogen, hydroxy, C₁₋₆ alkyl,—CF₃, —NH₂, —N(H)—W, or —N(W)₂;

-   -   each W is independently selected from —H, C₁₋₆ alkyl, aralkyl,        cycloalkyl or heterocyclic ring; each C₁₋₆ alkyl, aralkyl,        cycloalkyl or heterocyclic ring is optionally substituted with        1-3 of halogen, —OR⁶, —CN, C₁₋₆ alkyl or —NR¹⁸R¹⁹; or one W        group, together with the nitrogen atom to which it is attached        and a carbon atom of R, form a 4- to 8-membered ring; or two W        groups, together with the same or different nitrogen atom or        carbon atom to which they are attached, form a 4- to 8-membered        heterocyclic ring.

Some other embodiments of the compounds of this invention have one ormore of the following features: R⁷ is

one R⁸ is aryl, heteroaryl, C₃-C₈ cycloalkyl, or 4- to 8-memberedheterocyclic ring each optionally substituted with 1-3 of Q; R⁸ is a 4-to 8-membered heterocyclic ring optionally substituted with 1-3 of Q;one R⁸ is a 5- to 6-membered heterocyclic ring optionally substitutedwith 1-3 of Q; one R⁸ is a piperazine ring optionally substituted with1-3 of Q; one R⁸ is Q; Q is —NHW, —NW₂, —NH—SO₂W, —NH—COW, —CO—NHW,—CO—NW₂, —SO₂NHW, —SO₂—NW₂, —SW, —OW, or —W; Q is —NHW, —NW₂ or —OW; Wis C₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C₁₋₆alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionallysubstituted with 1-3 of halogen, —OR⁶, —CN, C₁₋₆ alkyl, C₁₋₆ alkyl or—NR¹⁸R¹⁹; W is C₁₋₆ alkyl or heterocyclic ring; each C₁₋₆ alkyl,aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with1-3 of halogen, —OR⁶, —CN, C₁₋₆ alkyl, C₁₋₆ alkyl or —NR¹⁸R¹⁹; one R⁸ is—R⁹, —OR⁹ or —N(R⁹)₂; R⁹ is independently H, C₃₋₆ carbocyclic ring, C₃₋₆heterocyclic ring, or C₁₋₃ aliphatic, wherein C₃₋₆ carbocyclic ring,C₃₋₆ heterocyclic ring and C₁₋₃ aliphatic are each optionallysubstituted with 1-3 Q; or two R⁹ groups, together with the N atom towhich they are bound, form a 4- to 8-membered ring optionally containingadditional 1 or 2 groups selected from —N(R¹⁷)—, —O—, or —S—, whereinthe 4- to 8-membered ring is optionally and independently substitutedwith 1-3 of W.

Still some other compounds of this invention have one or more of thefollowing features: R⁷ is a 4- to 10-membered heterocyclic monocyclic orbicyclic ring optionally substituted with 1-3 of R⁸; R⁷ is a 4- to6-membered heterocyclic monocyclic ring optionally substituted with 1-3of R⁸; R⁸ is Q; Q is selected from —C(O)—W, —C(O)—N(W)₂—C(O)—O—W or—SO₂—W; Q is selected from —C(O)—W.

Still some other compounds of this invention have one or more of thefollowing features: R⁷ is a C₃₋₈ carbocycle optionally substituted with1-3 R⁸; one R⁸ is Q; Q is selected from hydroxy, —NH₂, —N(H)—W, —N(W)₂,—N(H)—SO₂—W, —C(O)—N(W)₂, —N(H)—C(O)—W, or —O—C(O)—W; Q is selected from—N(H)—C(O)—W; R² is —NR¹⁰R¹¹; R¹⁰ is —H and R¹¹ is—C(R¹²R¹³)C(═O)NR¹⁴R¹⁵; R¹² is H; R¹³ is C₁₋₃ alkyl; R¹⁴ is H; and R¹⁵is alkyl substituted with trifluoromethyl or hydroxy, or R¹⁵ iscycloalkyl substituted with hydroxy; R¹⁵ is

Still some other compounds of this invention have one or more of thefollowing features: R² is −OR⁶ or —SR⁶; R⁶ is optionally substitutedphenyl.

Specific examples of the compounds of this invention include compoundsI-1 through I-304 or pharmaceutically acceptable salts thereof;compounds IA-0 through IA-13 or pharmaceutically acceptable saltsthereof; compounds II-0 through II-17 or pharmaceutically acceptablesalts thereof; and compounds EG4, EG5, EG6, EG7 and EG8 orpharmaceutically acceptable salts thereof. The structures of thesespecific compounds are show hereinafter.

In another aspect, the invention features compounds of formula Id

or a pharmacetucally acceptable salt thereof, wherein:

-   -   A is phenyl, pyridinyl, or pyrmidinyl;    -   B is —NR′R″;    -   R′ is H or C₁₋₄ alkyl;    -   R″ is a C₂₋₄ aliphatic substituted with —NH₂ or —NHCH₃; or    -   R″ is an N-heterocycloaliphatic optionally substituted on N with        CH₃; or    -   R′ and R″ together with the N to which they are attached form a        5- to 7-membered heterocycloaliphatic ring containing two N        atoms.

Compounds of formula Id show selectivity for PLK1 over PLK2 and PLK3.

In some embodiments, R¹ is trifluoromethyl.

In some embodiments, R′ is H or methyl and R″ is 2-amino- or2-methylamino-ethane.

In other embodiments, B is piperazinyl or diazepanyl, optionallysubstituted at the 4-position with methyl.

In certain embodiments, R′ is H or methyl, and R″ is pyrrolidine orpiperidine and is optionally substituted at N with methyl.

In certain embodiments, R″ is a C₂₋₄ aliphatic substituted with —NH₂ or—NHCH₃.

In certain embodiments, R″ is cyclohexyl substituted with —NH₂ or—NHCH₃.

In certain embodiments, R″ is piperazine or pyrrolidine.

The compounds of this invention include those described herein, and arefurther illustrated by the classes, subclasses, and species disclosedherein.

Another aspect of this invention provides a pharmaceutical compositioncontaining one of the compounds described above, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. The composition may furtherinclude another therapeutic agent selected from the group consisting ofsynthetic small molecule VEGF receptor antagonists, small moleculegrowth factor receptor antagonists, inhibitors of the EGF receptorand/or VEGF receptor and/or integrin receptors or any other proteintyrosine kinase receptors which are not classified under the syntheticsmall-molecules, inhibitors directed to EGF receptor and/or VEGFreceptor and/or integrin receptors or any other protein tyrosine kinasereceptors, which are fusion proteins, compounds which interact withnucleic acids and which are classified as alkylating agents or platinumcompounds, compounds which interact with nucleic acids and which areclassified as anthracyclines, as DNA intercalators or as DNAcross-linking agents, including DNA minor-groove binding compounds,anti-metabolites, naturally occurring, semi-synthetic or syntheticbleomycin type antibiotics, inhibitors of DNA transcribing enzymes, andespecially the topoisomerase I or topoisomerase II inhibitors, chromatinmodifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycleinhibitors, proteasome inhibitors, enzymes, hormones, hormoneantagonists, hormone inhibitors, inhibitors of steroid biosynthesis,steroids, cytokines, hypoxia-selective cytotoxins, inhibitors ofcytokines, lymphokines, antibodies directed against cytokines, oral andparenteral tolerance induction agents, supportive agents, chemicalradiation sensitizers and protectors, photo-chemically activated drugs,synthetic poly- or oligonucleotides, optionally modified or conjugated,non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodiestargeting growth factors or their receptors, antibodies targeting thesurface molecules of cancer cells, inhibitors of metalloproteinases,metals, inhibitors of oncogenes, inhibitors of gene transcription or ofRNA translation or protein expression, complexes of rare earth elements,compounds which reduces the transport of hyaluronan mediated by one ormore ABC transporters, and photo-chemotherapeutic agents.

Still, the pharmaceutical compositions of this invention may furthercontains another therapeutic agent selected from the group consisting ofa small molecule VEGF receptor antagonist such as vatalanib(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a dualEGFR/HER2 antagonist such as gefitinib, erlotinib, CI-1033 or GW-2016,an EGFR antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI-166,EKB-569, HKI-272 or herceptin, an antagonist of the mitogen-activatedprotein kinase such as BAY-43-9006 or BAY-57-9006, a quinazolinederivative such as4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineor4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,or a pharmaceutically acceptable salt thereof, a protein kinase receptorantagonist which is not classified under the synthetic small moleculessuch as atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab),IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, aprotein tyrosine kinase inhibitor which is a fusion protein such asVEGFtrap, an alkylating agent or a platinum compound such as melphalan,cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin,oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin,streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide,streptozocin, thiotepa, chlorambucil, a nitrogen mustard such asmechlorethamine, an ethyleneimine compound, an alkylsulphonate,daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil),epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin,distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin,CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, aphtalanilide such as propamidine or stilbamidine, an anthramycin, anaziridine, a nitrosourea or a derivative thereof, a pyrimidine or purineanalogue or antagonist or an inhibitor of the nucleoside diphosphatereductase such as cytarabine, 5-fluorouracile (5-FU), pemetrexed,tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine,mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin,hydroxyurea, or folic acid, a phleomycin, a bleomycin or a derivative orsalt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or aderivative thereof, a rifamycin, an actinomycin, adramycin, acamptothecin such as irinotecan or topotecan, an amsacrine or analoguethereof, a tricyclic carboxamide, an histonedeacetylase inhibitor suchas SAHA, MD-275, trichostatin A, CBHA, LAQ824, or valproic acid, ananti-cancer drug from plants such as paclitaxel (taxol), docetaxel ortaxotere, a vinca alkaloid such as navelbine, vinblastin, vincristin,vindesine or vinorelbine, a tropolone alkaloid such as colchicine or aderivative thereof, a macrolide such as maytansine, an ansamitocin orrhizoxin, an antimitotic peptide such as phomopsin or dolastatin, anepipodophyllotoxin or a derivative of podophyllotoxin such as etoposideor teniposide, a steganacin, an antimitotic carbamate derivative such ascombretastatin or amphetinile, procarbazine, a proteasome inhibitor suchas bortezomib, an enzyme such as asparaginase, pegylated asparaginase(pegaspargase) or a thymidine-phosphorylase inhibitor, a gestagen or anestrogen such as estramustine (T-66) or megestrol, an anti-androgen suchas flutamide, casodex, anandron or cyproterone acetate, an aromataseinhibitor such as aminogluthetimide, anastrozole, formestan orletrozole, a GNrH analogue such as leuprorelin, buserelin, goserelin ortriptorelin, an anti-estrogen such as tamoxifen or its citrate salt,droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of17.beta.-estradiol such as ICI 164,384 or ICI 182,780,aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, aLH-RH antagonist such as leuprolide, a steroid such as prednisone,prednisolone, methylprednisolone, dexamethasone, budenoside,fluocortolone or triamcinolone, an interferon such as interferon .beta.,an interleukin such as IL-10 or IL-12, an anti-TNF.alpha. antibody suchas etanercept, an immunomodulatory drug such as thalidomide, its R- andS-enantiomers and its derivatives, or revimid (CC-5013), a leukotrienantagonist, mitomycin C, an aziridoquinone such as BMY-42355, AZQ orEO-9, a 2-nitroimidazole such as misonidazole, NLP-1 or NLA-1, anitroacridine, a nitroquinoline, a nitropyrazoloacridine, a“dual-function” nitro aromatic such as RSU-1069 or RB-6145, CB-1954, aN-oxide of nitrogen mustard such as nitromin, a metal complex of anitrogen mustard, an anti-CD3 or anti-CD25 antibody, a toleranceinduction agent, a biphosphonate or derivative thereof such asminodronic acid or its derivatives (YM-529, Ono-5920, YH-529),zoledronic acid monohydrate, ibandronate sodium hydrate or clodronatedisodium, a nitroimidazole such as metronidazole, misonidazole,benznidazole or nimorazole, a nitroaryl compound such as RSU-1069, anitroxyl or N-oxide such as SR-4233, an halogenated pyrimidine analoguesuch as bromodeoxyuridine, iododeoxyuridine, a thiophosphate such asWR-272 1, a photo-chemically activated drug such as porfimer, photofrin,a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540(MC-540) or tin etioporpurin, an ant-template or an anti-sense RNA orDNA such as oblimersen, a non-steroidal inflammatory drug such asacetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen,fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin,zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac,ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac,oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminicacid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam,lomoxicam, nimesulide, meloxicam, celecoxib, rofecoxib, or apharmaceutically acceptable salt of a non-steroidal inflammatory drug, acytotoxic antibiotic, an antibody targeting the surface molecules ofcancer cells such as apolizumab or 1D09C3, an inhibitor ofmetalloproteinases such as TIMP-1 or TIMP-2, Zinc, an inhibitor ofoncogenes such as P53 and Rb, a complex of rare earth elements such asthe heterocyclic complexes of lanthanides, a photo-chemotherapeuticagent such as PUVA, an inhibitor of the transcription factor complexESX/DRIP130/Sur-2, an inhibitor of HER-2 expression, such as the heatshock protein HSP90 modulator geldanamycin and its derivative17-allylaminogeldanamycin or 17-AAG, a compound which reduces thetransport of hyaluronan mediated by one or more ABC transportersselected from a P-glycoprotein (P-gp) inhibitor molecule or inhibitorpeptide, an MRP 1 inhibitor, an antibody directed against and capable ofblocking the ABC transporter, an antisense oligomer, iRNA, siRNA oraptamer directed against one or more ABC transporters, or a therapeuticagent selected from IM-842, tetrathiomolybdate, squalamine, combrestatinA4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab,mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukindiftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,pipobroman, plicamycin, tamLoxifen and testolactone.

The pharmaceutical composition of this invention may still furthercontains another therapeutic agent selected from the group consisting ofan anti-cancer drug from plants such as paclitaxel (taxol), docetaxel ortaxotere, a vinca alkaloid such as navelbine, vinblastin, vincristin,vindesine or vinorelbine, a vinca alkaloid such as navelbine,vinblastin, vincristin, vindesine or vinorelbine, an alkylating agent ora platinum compound such as melphalan, cyclophosphamide, anoxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin,tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU),lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa,chlorambucil, a nitrogen mustard such as mechlorethamine, animmunomodulatory drug such as thalidomide, its R- and S-enantiomers andits derivatives, or revimid (CC-5013)), an ethyleneimine compound, analkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomaldoxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine,dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol,mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin,a phtalanilide such as propamidine or stilbamidine, an anthramycin, anaziridine, a nitrosourea or a derivative thereof, a pyrimidine or purineanalogue or antagonist or an inhibitor of the nucleoside diphosphatereductase such as cytarabine, 5-fluorouracile (5-FU), pemetrexed,tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine,mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin,hydroxyurea, or folic acid, an acridine or a derivative thereof, arifamycin, an actinomycin, adramycin, a camptothecin such as irinotecanor topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide,an histonedeacetylase inhibitor such as SAHA, MD-275, trichostatin A,CBHA, LAQ824, or valproic acid, a proteasome inhibitor such asbortezomib, a small molecule VEGF receptor antagonist such as vatalanib(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, anantagonist of the mitogen-activated protein kinase such as BAY-43-9006or BAY-57-9006, a dual EGFR/HER2 antagonist such as gefitinib,erlotinib, CI-1033 or GW-2016, an EGFR antagonist such as iressa(ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 or herceptin, aquinazoline derivative such as4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineor4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,or a pharmaceutically acceptable salt thereof, an inhibitor of thetranscription factor complex ESX/DRIP130/Sur-2, an inhibitor of HER-2expression, such as the heat shock protein HSP90 modulator geldanamycinand its derivative 17-allylaminogeldanamycin or 17-AAG, a protein kinasereceptor antagonist which is not classified under the synthetic smallmolecules such as atrasentan, rituximab, cetuximab, Avastin™(bevacizumab), IMC-1C11, erbitux (C-225), DC-1 01, EMD-72000, vitaxin,imatinib, a P-glycoprotein (P-gp) inhibitor molecule such as zosuquidar(LY 335973), its salts (especially the trichloride salt) and itspolymorphs, cyclosporin A, verapamil or its R-isomer, tamoxifen,quinidine, d-alpha tocopheryl polyethylene glycol 1000 succinate,VX-710, PSC833, phenothiazine, GF120918 (II), SDZ PSC 833, TMBY, MS-073,S-9788, SDZ 280-446, XR(9051) and functional derivatives, analogues andisomers of these, or an antibody targeting the surface molecules ofcancer cells such as apolizumab or ID09C3.

In some embodiments, the compositions of this invention may furtherinclude4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino-)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methyle-ne]-6-fluoro-2-indolinone,or a pharmaceutically acceptable salt thereof.

The compounds of this invention can be used to inhibit PLK proteinkinase activity in a biological sample.

Thus, the invention further provides a method of inhibiting PLK proteinkinase activity in a patient, which includes administering to thepatient one of the compounds described above or one of the compositionsdescribed above.

Another aspect of this invention provides a method of treating aproliferative disorder, a neurodegenerative disorder, an autoimmunedisorder, an inflammatory disorder, or an immunologically mediateddisorder in a patient. The method includes administering to the patientin need thereof a therapeutically effective amount of one of thecompounds or compositions described above. This method may furtherinclude administering to the patient an additional therapeutic agentselected from a chemotherapeutic or anti-proliferative agent, ananti-inflammatory agent, an immunomodulatory or immunosuppressive agent,a neurotrophic factor, an agent for treating cardiovascular disease, anagent for treating destructive bone disorders, an agent for treatingliver disease, an anti-viral agent, an agent for treating blooddisorders, an agent for treating diabetes, or an agent for treatingimmunodeficiency disorders, wherein (1) said additional therapeuticagent is appropriate for the disease being treated, and (2) saidadditional therapeutic agent is administered together with saidcomposition as a single dosage form or separately from said compositionas part of a multiple dosage form.

Still in another aspect, the invention provides a method of treating anoncological disease in a patient, which includes administering to thepatient in need thereof a therapeutically effective amount of a compoundor a pharmaceutical composition of those described above. Examples ofthe oncological disease include, but are not limited to, refractory orrelapsed multiple myeloma, acute or chronic myelogenous leukaemia,myelodysplastic syndrome, myeloproliferativesyndromes, acutelymphoblastic leukaemia, Hodgkin's and non-Hodgkin's lymphoma.

The invention further provides a method of treating solid tumor,melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancerselected from colon, breast, gastric, ovarian, cervical, lung, centralnervous system (CNS), renal, prostate, bladder, or pancreatic, in apatient by administering to said patient one of the compounds orpharmaceutical compositions described above.

The invention still further provides a method of treating cancer in apatient, which includes administering to the patient one of thecompounds or pharmaceutical compositions described above. Examples ofthe cancer include urogenital cancer, lung cancer, gastrointestinalcancer, head and neck cancer, malignant mesothelioma, breast cancer,malignant melanoma, childhood cancer and bone or soft tissue sarcoma.

The invention also relates to a method of treating a disease involvingcell proliferation, migration or apoptosis of cancer cells, orangiogenesis, in a human or non-human mammalian body, by administeringsimultaneously, separately or sequentially to the patient atherapeutically effective amount of one of the compounds orpharmaceutical compositions described above. Examples of such diseaseinclude Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupuserythematosus (SLE), Sjögren's syndrome, multiple sclerosis (MS),Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenicpurpura, and rheumatoid arthritis (RA).

Also within the scope of the invention is a process for preparing acompound of formula I

or a pharmaceutically acceptable salt thereof, wherein the variables R¹and R² are as defined above. This process includes contacting a mixtureof a boronate ester of formula 8

(wherein each R′ is independently C₁-C₃ alkyl or two R′ together withthe atoms to which they are attached fom a 5 or 6 membered ringoptionally substituted with 1 to 4 methyl groups), a pyrimidine offormula 7

and an alkali metal carbonate with a palladium catalyst in a suitablesolvent. An example of the suitable palladium catalyst isbis-(tri-tert-butylphosphine)palladium(0) and an example of the suitablesolvent is dioxane and the alkali metal carbonate is potassiumcarbonate. To practice this process, the pyrimidine can be4-chloro-2-(methylthio)pyrimidine-5-carbonitrile, and the boronate estercan be5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

In some embodiments of the process of this invention, R² is —SCH₃.

The process of this invention may further includes the steps of:

-   -   (a) oxidizing a compound of formula 26

(wherein R¹ is as previously described) with chlorine in aqueous ethanolto provide a compound of formula 27

-   -   (b) reacting a compound of formula 27 with a compound of formula        R²H, wherein R² is HNR⁴R⁵, HOR⁶ or HSR⁶ and R⁴, R⁵ and R⁶ are as        previously described, in the presence of microwave irradiation        to provide a compound of formula 28

and

-   -   c) removing the Tos protecting group to provide compounds of        formula I.

DEFINITIONS

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 75th Ed. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. andMarch, J., John Wiley & Sons, New York: 2001, the entire contents ofwhich are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), branched, or cyclic substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups. Specific examples include, but are notlimited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl,n-butenyl, ethynyl, and tert-butyl.

As used herein, the term “C₀₋₃ alkyl” refers to either a bond or a C₁₋₃alkyl. Other carbon number ranges containing zero have the same meaning.

It should be understood that if the aliphatic is alkenyl or alkynyl,then the aliphatic group has at least 2 carbon atoms.

The term “oxo” for substitutent refers to the group “═O” which replace,e.g., two hydrogen atoms on a carbon atom of a methylen group to form—C(O)— (equivalent to —C(═O)—), i.e., a carbonyl group.

The term “cycloaliphatic” or “carbocyclic” refers to a monocyclic C₃₋₈hydrocarbon or bicyclic C₇₋₁₂ hydrocarbon that is completely saturatedor that contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members. Suitable cycloaliphatic groups include, but are not limitedto, cycloalkyl, bicycloalkyl, cycloalkenyl and bicycloalkenyl groups.Specific examples include, but are not limited to, cyclohexyl,bicycle[2.2.1]heptanyl, cyclopropenyl, and cyclobutyl. The term“heteroaliphatic”, as used herein, means aliphatic groups wherein one ortwo carbon atoms are independently replaced by one or more of oxygen,sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may besubstituted or unsubstituted, branched or unbranched, cyclic or acyclic,and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans nonaromatic, monocyclic, bicyclic, or tricyclic ring systems inwhich one or more ring members are an independently selected heteroatom.A heterocyclic ring includes heterocycloaliphatic, which in turnincludes heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl.In some embodiments, the “heterocycle”, “heterocyclyl”, or“heterocyclic” group has three to fourteen ring members in which one ormore ring members is a heteroatom independently selected from oxygen,sulfur, nitrogen, or phosphorus, and each ring in the system contains 3to 7 ring members.

Suitable heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrazolinyl,3-pyrazolinyl, 4-pyrazolinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g., cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus, (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “nonaromatic”, as used herein, describes rings that are eithersaturated or partially unsaturated.

The term “aromatic”, as used herein, describes rings that are fullyunsaturated.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F,Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Suitable heteroaryl rings include, but arenot limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

When the term “ortho”, “meta”, or “para” is used to identify theposition of a substituent on a 6-member ring system, it is relative tothe atom by which this ring system is attached to the core of thecompound of formula. For instance, a phenyl substituted at theortho-position with methyl, at the meta-position with fluoro, and at thepara-position with isopropyl is

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired reactive sites in a multifunctional compound. In certainembodiments, a protecting group has one or more, or preferably all, ofthe following characteristics: a) is added selectively to a functionalgroup in good yield to give a protected substrate that is b) stable toreactions occurring at one or more of the other reactive sites; and c)is selectively removable in good yield by reagents that do not attackthe regenerated, deprotected functional group. Exemplary protectinggroups are detailed in Greene, T. W., Wuts, P. G in “Protective Groupsin Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999(and other editions of the book), the entire contents of which arehereby incorporated by reference. The term “nitrogen protecting group”,as used herein, refers to an agents used to temporarily block one ormore desired nitrogen reactive sites in a multifunctional compound.Preferred nitrogen protecting groups also possess the characteristicsexemplified above, and certain exemplary nitrogen protecting groups arealso detailed in Chapter 7 in Greene, T. W., Wuts, P. G in “ProtectiveGroups in Organic Synthesis”, Third Edition, John Wiley & Sons, NewYork: 1999, the entire contents of which are hereby incorporated byreference.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with said otheratom or group. Examples of such atoms or groups would include, but arenot limited to, —NR—, —O—, —S—, CO₂—, —OC(O)—, —C(O)CO—, —C(O)—,—C(O)NR—, —C(═N—CN)—, —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, —NRSO₂NR—, —SO—, or —SO₂—, wherein R is defined herein.Unless otherwise specified, the optional replacements form a chemicallystable compound. Optional interruptions can occur both within the chainand at either end of the chain; i.e., both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound. The optional interruptions or replacementscan also completely replace all of the carbon atoms in a chain. Forexample, a C₃ aliphatic can be optionally interrupted or replaced by—NR—, —C(O)—, and —NR— to form —NRC(O)NR— (a urea).

As used herein, the term “1-3” (or other similar numerical terms) refersto a range of 1 to 3.

Unless otherwise specified, if the replacement or interruption occurs atthe terminal end, the replacement atom is bound to an H on the terminalend. For example, if —CH₂CH₂CH₃ were optionally interrupted with —O—,the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Unless otherwise stated, a substituent can freely rotate around anyrotatable bonds. For example, a substituent drawn as

also represents

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

The following abbreviations are used:

-   -   PG protecting group    -   LG leaving group    -   DCM dichloromethane    -   Ac acetyl    -   DMF dimethylformamide    -   EtOAc ethyl acetate    -   DMSO dimethyl sulfoxide    -   MeCN acetonitrile    -   TCA trichloroacetic acid    -   ATP adenosine triphosphate    -   EtOH ethanol    -   Ph phenyl    -   Me methyl    -   Et ethyl    -   Bu butyl    -   DEAD diethylazodicarboxylate    -   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid    -   BSA bovine serum albumin    -   DTT dithiothreitol    -   MOPS 4-morpholinepropanesulfonic acid    -   NMR nuclear magnetic resonance    -   HPLC high performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   TLC thin layer chromatography    -   Rt retention time

Synthesis of the Compounds

The compounds of this invention may, in general, be prepared by methodssuch as those depicted in the schemes below. Unless otherwise indicated,all variables in the following schemes are as defined herein.

Referring to Scheme 1, oxidation of compound 1 to provide compound 2 canbe achieved with a known oxidizing agent such as oxone or m-CPBA orchlorine gas in a solvent such as aqueous alcohol, acetonitrile ordichloromethane. Displacement with R²—H, wherein R²—H is HNR⁴R⁵, HOR⁶ orHSR⁶, to give compound 3 can be achieved thermally or using microwaveheating in a solvent such as dioxane, tetrahydrofuran, ethanol,isopropanol or butanol.

An alternative method for preparing compounds of the invention isillustrated in Scheme 2.

Referring to Scheme 2, hydrolysis of compound 1 can be achieved by waterin the presence of a base such as triethylamine or ethyldiisopropylaminein a solvent such as acetonitrile, tetrahydrofuran or dioxane to providecompound 2-2. Chlorination of compound 2-2 to provide compound 2-3 canbe achieved by phosphorous oxychloride in a solvent such as toluene.Reaction of compound 2-3 with R²—H, wherein R²—H is HNR⁴R⁵, HOR⁶ orHSR⁶, can be achieved thermally or using microwave heating in a solventsuch as dioxane, tetrahydrofuran, ethanol, isopropanol or butanol toprovide compound I.

In some instances, the azaindole 1-nitrogen is optionally protected withan arylsulphonate, such as tosyl or benzene sulphonate, a silyl groupsuch as tert-butyldimethylsilyl or triisopropylsilyl, or is leftunprotected. If the nitrogen is protected by a sulphonate group then itcan be removed in a subsequent step by treatment with base such asaqueous sodium hydroxide, lithium hydroxide or potassium carbonate in asolvent such as methanol, ethanol or isoproanol. If the nitrogen isprotected by a silyl group then it can be removed in a subsequent stepby treatment with aqueous acid such as hydrochloric acid or sulphuricacid in a solvent such as methanol, ethanol, isopropanol,tetrahydrofuran or dioxane.

An alternative method for preparing compounds of the invention is shownin Scheme 3.

Referring to Scheme 3, oxidation of compound 4 can be achieved by arange of standard oxidising agents such as oxone or mCPBA in a solventsuch as acetonitrile or dichloromethane. Reaction of compound 5 withcompound 6 may be carried as described in Scheme Ito provide compound 7.The coupling reaction of compound 7 with compound 8, wherein —B(OR′)₂can be a boronic acid —B(OH)₂), a boronate ester such as —B(OMe)₂ or acyclic boronate ester such as

provides compound I.

The azaindole nitrogen may be protected with an arylsulphonate, such astosyl or benzene sulphonate, a silyl group such astert-butyldimethylsilyl or triisopropylsilyl, or is left unprotected. Ifthe nitrogen is protected by a sulphonate group then it can be removedin a subsequent step by treatment with base such as aqueous sodiumhydroxide, lithium hydroxide or potassium carbonate in a solvent such asmethanol, ethanol or isoproanol. If the nitrogen is protected by a silylgroup then it can be removed in a subsequent step by treatment withaqueous acid such as hydrochloric acid, sulphuric acid in a solvent suchas methanol, ethanol, isoproanol, tetrahydrofuran or dioxane.

Compounds of the invention wherein R¹ is —NHR and R is aryl may beprepared as illustrated in Scheme 4.

Referring to Scheme 4, reaction of the bromoazaindole compound 9 withammonia provides the amine compound 10. After protection of compound 10as a Cbz derivative compound 11, bromination provides the bromo compound12. Protection of the azaindole 1-nitrogen as a tosylate derivativeprovides compound 13 which is converted to the boronate compound 14.Coupling of compound 14 with the chloropyrimidine 4 in the presence of apalladium catalyst provides compound 15. Oxidation and displacement aspreviously described provides compound 17. Removal of the Cbz group andcoupling with an aryl boronate as described above provides compound 19.Removal of the tosyl group provides compounds of the invention I.

In one method, the azaindole boronate esters 8 may be prepared asillustrated in Scheme 5.

Referring to Scheme 5, an aminopyridine compound 20 is iodinated toprovide the iodo compound 21. Reaction of compound 21 withtrimethylsilylacetylene provides compound 22 which can be cyclized toprovide the azaindole compound 23. Protection of compound 23 as atosylate followed by bromination provides the bromoazaindole compound25. Reaction of compound 25 with a diboronate in the presence of apalladium catalyst provides boronate intermediates compound 8.

Another method for preparing the compounds is illustrated in Scheme 6.

Referring to Scheme 6, coupling of compound 8 with the chloropyrimidinecompound 4 in the presence of a palladium catalyst provides compound 26.Oxidation by m-CPBA or chlorine and displacement as previously describedprovides compound 28. Compounds of formula I of this invention areobtained by removal of the tosyl group.

In some embodiments, the compounds may be prepared as illustrated inScheme 7.

Referring to Scheme 7, hydrolysis of compound 27 (n=2) furnishescompound 29 which is chlorinated under conditions known in the art toprovide compound 30. Displacement of chloropyrimidine compound 30 withan appropriate R²—H, as previously described, provides compound 28.Compounds of formula I of this invention are obtained by removal of thetosyl group.

In other embodiments, the compounds may be prepared as illustrated inScheme 8.

Referring to Scheme 8,

represents a 4 to 8 membered optionally substituted nitrogen heterocyclewherein PG is a protecting group. Reaction of compound 27 with aminecompound 31 followed by deprotection provides compound 33. Furthermodifications of compound 33 may be achieved by known reactions such as,for example, acylation, alkylation, and reductive amination to provideintermediates compound 34. Compounds of formula Ia of this invention arethen obtained by removal of the tosyl group.

In certain embodiments, compounds of the invention are prepared bymodification of substituents as illustrated in Scheme 9.

Referring to Scheme 9, hydrogenation of compound 35 in the presence ofPt0₂ furnishes compound 36. Reaction of compound 30 with amine compound36 provides compound 37. Subsequent oxidation of alcohol compound 37 tocompound 38 followed by reductive amination of compound 38 providescompound 39. Further modifications of compound 39 may be achieved byknown reactions such as, for example, acylation, alkylation, andreductive amination to provide intermediates compound 40. Compounds offormula Ib of this invention are then obtained by removal of the tosylgroup.

In other embodiments, compounds of the invention are prepared bymodification of substituents as illustrated in Scheme 10.

Referring to Scheme 10, reaction of compound 27 with an amine compound41, wherein Hal represents F, Cl, Br or I and each X is independentlyCR⁸ or N, provides compound 42. Reaction of compound 42 with H-K whereinK is −OR⁶, —SR⁶, or —N(R⁹)₂ can be achieved thermally using conventionalheating or microwave irradiation, in a solvent such as dioxane,tetrahydrofuran, ethanol, isopropanol or butanol. In the case where H-Kis HN(R⁹)₂ the reaction can be achieved via Buchwald couplingconditions. Compounds of formula Ic of this invention are then obtainedby removal of the tosyl group of compound 43. The chiral version ofcompound 41 can be prepared using known methods: Tetrahedron Asymmetry2006, 17, 3163-9.

An alternative method for preparing the compounds is illustrated inScheme 11.

Referring to Scheme 11, reaction of compound 27 with pentafluorophenolprovides compound 44, which can be displaced with a series of HNR²,under similar conditions as described previously in Scheme 10. Compoundsof formula I of this invention are obtained by removal of the tosylgroup of compound 28.

A further method for preparing the compounds is illustrated in Scheme12.

Referring to Scheme 12, reaction of compound 29 withdiethylchlorophosphate provides compound 45. Reaction of compound 45with HR² under conditions similar to those previously described providesthe intermediate compound 28. Compounds of formula I of this inventionare then obtained by removal of the tosyl group of compound 28.

An alternative method for preparing compounds of fomula Ib isillustrated in Scheme 13.

Referring to Scheme 13, hydrogenation of compound 46, wherein PG is asuitable protecting group (e.g. Boc), in the presence of rhodium onalumina furnishes compound 47. Activation of alcohol compound 47 with asuitable leaving group LG1 (e.g., Tos or Mes) to provide compound 48followed by a reaction with NaN₃ provides compound 49. After reductionof the azide compound 49, amine compound 50 is coupled with a range ofW-X by reactions known in the art to give derivatives compound 51.Compounds of formula Ib of this invention are obtained by reaction ofdeprotected amine compound 52 with a compound of e.g. formula 27,followed by removal of the tosyl group.

Another method for preparing compounds of formula Ia is shown in Scheme14.

Referring to Scheme 14, each X is independently CR⁸ or N and R^(8a) isR⁸ or two R^(8a) together with the atom to which they are attached mayform a 5- to 7-membered heterocyclic ring. Starting material 53 (see,e.g., Bioorg. Med. Chem., 2005, 13, 6763) is lithiated and reacted withketones R^(8a)C(O)R^(8a). Amines compound 56 are formed afterdeprotection of ketals compound 54, followed by reductive amination ofintermediates compound 55. Reaction of compound 56 with compound 27provides intermediate compound 57. Compounds of formula Ia of thisinvention are obtained by removal of the tosyl group.

Schemes 1 through 14 above depict synthetic methods that may be used toprovide compounds of this invention. Accordingly, this invention alsoprovides processes for preparing a compound of this invention accordingto Schemes 1 through 14.

Use of the Compounds

The present invention provides compounds that are useful for thetreatment of diseases, disorders, and conditions including, but notlimited to, autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. Another aspect of this inventionprovides compounds that are inhibitors of protein kinases, and thus areuseful for the treatment of the diseases, disorders, and conditions,along with other uses described herein. In another aspect of the presentinvention, pharmaceutically acceptable compositions are provided,wherein these compositions comprise any of the compounds as describedherein, and optionally comprise a pharmaceutically acceptable carrier,adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable salt or pharmaceutically acceptablederivative thereof.

As used herein, a “pharmaceutically acceptable derivative” is an adductor derivative which, upon administration to a patient in need, iscapable of providing, directly or indirectly, a compound as otherwisedescribed herein, or a metabolite or residue thereof. Examples ofpharmaceutically acceptable derivatives include, but are not limited to,pharmaceutically acceptable prodrugs.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds. Acid addition saltscan be prepared by first reacting the purified compound in itsfree-based form with a suitable organic or inorganic acid, and thenisolating the salt thus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate,heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,salicylate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like. Saltsderived from appropriate bases include alkali metal, alkaline earthmetal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisionsthe quaternization of any basic nitrogen-containing groups of thecompounds disclosed herein. Water or oil-soluble or dispersible productsmay be obtained by such quaternization.

Base addition salts can be prepared by first reacting the purifiedcompound in its acid form with a suitable organic or inorganic base, andthen isolating the salt thus formed. Base addition salts include alkalior alkaline earth metal salts. Representative alkali or alkaline earthmetal salts include sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable acid or base addition salts.

As described herein, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother nontoxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

One aspect of this invention provides a method for the treatment orlessening the severity of a disease selected from an autoimmune disease,an inflammatory disease, a proliferative or hyperproliferative disease,such as cancer, an immunologically-mediated disease, a bone disease, ametabolic disease, a neurological or neurodegenerative disease, acardiovascular disease, allergies, asthma, Alzheimer's disease, or ahormone related disease, comprising administering an effective amount ofa compound, or a pharmaceutically acceptable composition comprising acompound, to a subject in need thereof. The term “cancer” includes, butis not limited to the following cancers: breast; ovary; cervix;prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma;neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoidcarcinoma, large cell carcinoma, small cell carcinoma, lungadenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma; thyroid,follicular carcinoma, undifferentiated carcinoma, papillary carcinoma;seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma andbiliary passages; kidney carcinoma; myeloid disorders; lymphoiddisorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral),lip, tongue, mouth, pharynx; small intestine; colon-rectum, largeintestine, rectum; brain and central nervous system; and leukemia.

In certain embodiments, an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective inorder to treat said disease. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of said disease. In some embodiments, saiddisease is selected from a proliferative disorder, a neurodegenerativedisorder, an autoimmune disorder, and inflammatory disorder, and animmunologically-mediated disorder. In some embodiments, said disease isa proliferative disorder. In some embodiments, said disease is cancer.

In other embodiments of this invention, said disease is a protein-kinasemediated condition. In some embodiments, said protein kinase in PLK.

The term “protein kinase-mediated condition”, as used herein means anydisease or other deleterious condition in which a protein kinase plays arole. Such conditions include, without limitation, autoimmune diseases,inflammatory diseases, proliferative and hyperproliferative diseases,immunologically-mediated diseases, bone diseases, metabolic diseases,neurological and neurodegenerative diseases, cardiovascular diseases,hormone related diseases, allergies, asthma, and Alzheimer's disease.

The term “PLK-mediated condition”, as used herein means any disease orother deleterious condition in which PLK plays a role. Such conditionsinclude, without limitation, a proliferative disorder, such as cancer, aneurodegenerative disorder, an autoimmune disorder, and inflammatorydisorder, and an immunologically-mediated disorder.

In some embodiments, the compounds and compositions of the invention areinhibitors of protein kinases. As inhibitors of protein kinases, thecompounds and compositions of this invention are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere a protein kinase is implicated in the disease, condition, ordisorder. In one aspect, the present invention provides a method fortreating or lessening the severity of a disease, condition, or disorderwhere a protein kinase is implicated in the disease state. In anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereinhibition of enzymatic activity is implicated in the treatment of thedisease. In another aspect, this invention provides a method fortreating or lessening the severity of a disease, condition, or disorderwith compounds that inhibit enzymatic activity by binding to the proteinkinase. In some embodiments, said protein kinase is PLK.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radiolabelling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.

The protein kinase inhibitors or pharmaceutical salts thereof may beformulated into pharmaceutical compositions for administration toanimals or humans. These pharmaceutical compositions, which comprise anamount of the protein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areanother embodiment of the present invention. In some embodiments, saidprotein kinase-mediated condition is a PLK-mediated condition. In someembodiments, a PLK1-mediated condition.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable ester, salt of an ester or other derivativeof a compound of this invention which, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favoured derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

According to another embodiment, the invention provides methods fortreating or preventing a protein kinase-mediated condition (in someembodiments, a PLK-mediated condition) comprising the step ofadministering to a patient one of the above-described pharmaceuticalcompositions. The term “patient”, as used herein, means an animal,preferably a human.

Preferably, that method is used to treat or prevent a condition selectedfrom cancers such as cancers of the breast, colon, prostate, skin,pancreas, brain, genitourinary tract, lymphatic system, stomach, larynxand lung, including lung adenocarcinoma and small cell lung cancer;stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer'sdisease, cystic fibrosis, and viral disease, or any specific diseasedescribed above.

Another aspect of the invention relates to inhibiting protein kinaseactivity in a patient, which method comprises administering to thepatient a compound of formula I or a composition comprising saidcompound.

Depending upon the particular protein kinase-mediated conditions to betreated or prevented, additional drugs, which are normally administeredto treat or prevent that condition, may be administered together withthe inhibitors of this invention. For example, chemotherapeutic agentsor other anti-proliferative agents may be combined with the proteinkinase inhibitors of this invention to treat proliferative diseases.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the protein kinase inhibitor-containingcompound or composition. Alternatively, those agents may be part of asingle dosage form, mixed together with the protein kinase inhibitor ina single composition.

In some embodiments, said protein kinase inhibitor is a PLK kinaseinhibitor. In other embodiments, said protein kinase inhibitor is a PLK1kinase inhibitor.

This invention may also be used in methods other than those involvingadministration to a patient.

One aspect of the invention relates to inhibiting protein kinaseactivity in a biological sample or a patient, which method comprisescontacting said biological sample with a compound of formula I or acomposition comprising said compound. The term “biological sample”, asused herein, means an in vitro or an ex vivo sample, including, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of protein kinasesin biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Those compounds may be analyzed byknown methods, including but not limited to LCMS (liquid chromatographymass spectrometry) and NMR (nuclear magnetic resonance). Compounds ofthis invention may be also tested according to these examples. It shouldbe understood that the specific conditions shown below are onlyexamples, and are not meant to limit the scope of the conditions thatcan be used for making, analyzing, or testing the compounds of thisinvention. Instead, this invention also includes conditions known tothose skilled in that art for making, analyzing, and testing thecompounds of this invention.

All references cite in this document are incorporated herein byreference.

EXAMPLES

Mass spec. samples may be analyzed on a MicroMass Quattro Micro massspectrometer operated in single MS mode with electrospray ionization.Samples may be introduced into the mass spectrometer usingchromatography.

¹H-NMR spectra may be recorded at 400 MHz using a Bruker DPX 400instrument.

Preparation 1:5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

Step 1: 3-Iodo-5-Trifluoromethylpyridin-2-amine

To 2-amino 5-trifluoromethylpyridine, (50 g, 308 mmol) was added aceticacid (500 mL), followed by pre-mixed water (35 mL) and concentratedsulfuric acid (5 mL) and stirred until completely solubilised. Periodicacid (13.3 g, 58 mmol) was added followed by iodine (31.2 g, 123 mmol)and then the reaction mixture was heated to 85° C. for 18 hours.

The reaction mixture was allowed to cool to room temperature and thencarefully basified with 4M NaOH solution to pH 10-14. This gave aprecipitate which was isolated by filtration and stirred in water (1litre), filtered and dried to give the product as a brown powder (61.38g, 69%).

Step 2: 5-Trifluoromethyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a stirred solution of 3-Iodo-5-trifluoromethylpyridin-2-amine (61.38g, 213 mmol) in anhydrous THF (200 mL) under a nitrogen atmosphere wasadded Pd(PPh)₃Cl₂ (1.5 g, 2.1 mmol), and copper iodide (0.406 g, 2.1mmol) and the reaction mixture degassed under nitrogen. The reactionmixture was cooled in an ice bath and TMS acetylene (36 mL, 256 mmol)was added dropwise over 30 minutes. Upon complete addition the reactionwas allowed to warm to room temperature and monitored until the reactionwas complete. The mixture was diluted with ethyl acetate (200 mL) andfiltered through silica washed through with 4×150 mL ethyl acetate. Thefiltrates were concentrated and the solid was triturated from heptane(250 mL) to give 56 g of product.

Step 3: 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine

To a stirred solution of potassium tert-butoxide (53.6 g, 479 mmol) inanhydrous NMP (200 mL) under a nitrogen atmosphere at 80° C. was added asolution of 5-trifluoromethyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine(62 g, 239 mmol) in NMP (100 mL) at a rate to maintain the internaltemperature below 100° C. After complete addition the reaction wasdeemed complete by LCMS. The reaction mixture was allowed to cool toroom temperature and poured carefully into saturated brine (700 mL)cooled in an ice bath to 10° C. The precipitate that formed was aged for45 min at this temperature and isolated by filtration through buchnerfunnel. The collected precipitate was stirred in ethyl acetate (1 litre)and water then filtered through celite to remove insoluble polymericmaterial and organic layer was separated. The aqueous layer was furtherextracted with ethyl acetate and the combined organic layers dried overmagnesium sulfate and concentrated to give a brown solid which wastriturated by stirring for an hour in hot heptane and then coolingbefore filtration, to afford 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridineas a crystalline solid (26.38 g, 59% yield).

Step 4: 5-Trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a stirred solution of sodium hydride (6.2 g, 156 mmol, 60%dispersion), tosyl chloride (27 g, 141.8 mmol), in anhydrous THF (200mL) under a nitrogen atmosphere was added a solution of5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (26.38 g, 141.8 mmol) in THF(150 mL) dropwise at a rate which maintained the internal temperature ofthe reaction below 40° C. The reaction mixture was stirred overnight atroom temperature and analysis by LCMS showed no starting materialremained after this time. The reaction mixture was concentrated toremove most of THF and diluted with DCM and water. The organic layer wasseparated and the aqueous layer further extracted with DCM. The organiclayers are combined and washed with brine, dried over magnesium sulphateand concentrated to a volume which was appropriate to load onto the topof a silica plug (300 mL) pre-wet with DCM, and the silica was washedwith 2.5 L DCM. The filtrate was concentrated to give the product as aslightly brown solid (44.1 g, 92% yield).

Step 5: 3-Bromo-5-Trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a stirred solution of5-trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (53.7 g, 158 mmol)in DCM (250 mL) was added a solution of bromine (16 mL, 316 mmol) in DCM(50 mL) dropwise. No significant exotherm was observed. After an hour atroom temperature, the reaction mixture had thickened and stirringceased. The reaction was deemed complete by tlc and was diluted with 1.2litres of DCM and 50:50 saturated bicarbonate: saturated sodiumthiosulfate aqueous solution. The organic layer was separated andfurther washed with the 50:50 aqueous mixture, dried over magnesiumsulfate and evaporated. The crude yellow solid was triturated withdiethyl ether and solid isolated and dried to give the product as ayellow powder (59 g, 59% yield)

Step 6:5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a mixture of3-Bromo-5-trifluoromethyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (5 g, 11.9mmol), bis-(pinacolato)diboron (40 g, 95.5 mmol), potassium acetate(28.1 g, 266.7 mmol) was added 1,4-dioxane (800 mL). The reactionmixture was stirred vigorously while nitrogen gas was purged through thesolution for 2 hours. After this time tetrakis(triphenylphosphine)palladium (10 mol %) was added in one portion and the reaction mixturebrought to reflux after an hour. After 4 hours moretetrakis(triphenylphosphine)palladium (10 mol %) added and the reactionmixture refluxed under nitrogen overnight. Heating continued until TLCconfirmed no starting material remained. The reaction mixture wasallowed to cool then diluted with an equivalent volume of petroleumether. Solid potassium acetate was removed by filtration through celite.The filtrate was evaporated to dryness and the residue suspended in 20%ethyl acetate 80% petroleum ether and filtered through a plug ofFlorisil, eluting with 3 volumes followed by one volume 30% ethylacetate 70% petroleum ether. The mixture was concentrated and trituratedwith heptane to give an off-white powder (35.72 g, 80% yield)

Preparation 2:2-(methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

A mixture of5-trifluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(415 mg, 1.08 mmol, 1.0 Eq.) and4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (146 mg, 1.08 mmol, 1.0Eq.) was suspended in toluene (20 mL) and EtOH (5 mL) and treated with2M K₂CO₃ (1.62 mL, 3.24 mmol, 3.0 Eq.). The mixture was sonicated underan atmosphere of nitrogen for 20 min and then treated with Pd(PPh₃)₄ (75mg, 0.06 mmol, 0.1 eq.). After sonication for a further 5 minutes thereaction was heated under microwave conditions at 130° C. for 15minutes. The reaction was diluted with EtOAc and washed with brine. Theorganic phase was dried over Mg50₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography (ISCO Companion™, 80 gcolumn, 0-100% EtOAc/Petroleum Ether). The product was seen toprecipitate out in the collection tubes and was filtered off. Furtherproduct was obtained by concentration of the fractions and triturationwith Et₂O to give the title compound as an off-white solid (195 mg,40%).

Preparation 2a:2-(methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile;alternate procedure

5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(50 g, 107.2 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile(39.8 g, 214.4 mmol) were dissolved in dioxane (900 mL). Potassiumcarbonate (44.45 g, 321.6 mmol) was added followed by water (135 mL).The mixture was degassed 3 times with vacuum/nitrogen cycles, thenbis-(tri-tert-butylphosphine)palladium(0) (Strem, 5.0 g, 9.78 mmol) wasadded. After 30 minutes an additional 50 mL of water was added. A thickprecipitate formed. The mixture was filtered and the product washed withwater. The product was dried in a vacuum oven at 60° C. for 18 hours.This gave2-(methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileas an off-white solid (48.1 g, 91%).

¹H NMR (DMSO-d₆, 400 MHz) δ 2.07 (3H, s), 2.65 (3H, s), 7.49 (2H, d),8.12 (2H, d), 8.93 (1H, s), 9.03 (1H, s), 9.12 (1H, s), 9.17 (1H, s); MS(ES⁺) 490, (ES⁻) 488.

Preparation 3:2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(50 mg, 0.1 mmol) in DCM (10 mL) was treated with MCPBA (38 mg, 0.22mmol, 2.2 Eq) and allowed to stir overnight at room temperature. Themixture was concentrated in vacuo and treated with EtOAc. The insolublematerial was filtered off and the resultant filtrate was concentrated togive the title compound which was taken forward (33 mg, 63%).

Example 12-(benzylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(50 mg, 0.096 mmol) was heated with benzylamine (2 luL, 0.19 mmol, 2.0Eq.) and DIPEA (50 uL, 0.29 mmol, 3.0 Eq.) in THF (2 mL) under microwaveconditions at 100° C. for 10 minutes. The reaction was concentrated andthe residue dissolved in THF (5 mL). LiOH.H₂O (20 mg, 0.48 mmol, 5.0Eq.) in water (1 mL) was added and the reaction stirred for 1 hour. Thereaction mixture was concentrated and the residue treated with MeOH. Theobtained white precipitate was isolated by filtration and dried undervacuum (13 mg, 36% over 2 steps).

MS (ES⁺) m/e=395. ¹H NMR (DMSO) 4.67 (2H, d), 4.74 (2H, d), 7.21-7.38(10H, m), 8.68 (1H, s), 8.72-8.74 (5H, m), 8.86 (1H, t), 8.93 (1H, s),9.03 (1H, t), 9.27 (1H, s), 12.77 (2H, vbrs). [1:1 Mixture of rotamers]

Example 22-((R)-1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-147 and2-((S)-1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(I-129)

Step 1:2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(Methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(1.4 g, 2.86 mmol) was suspended in ethanol (60 mL) and water (4 mL).The mixture was cooled in an ice bath, and chlroine gas was slowlybubbled through the solution for 20 minutes. After addition, thesuspension was stirred for another 30 minutes at 0° C. The reactionmixture was allowed to vent for 15 minutes, then, ether (100 mL) wasadded and the solid was filtered off. The solid was dried under vacuo togive a light pink solid (1.3 g, 87% yield).

MS (ES⁺) 522.

Step 2:2-((R)-(1-(6-chloropyridin-3-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Diisopropylethylamine (730 μl, 4.2 mmol) was added to a mixture of2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(330 mg, 2.1 mmol) and 1-(6-chloropyridin-3-yl)ethanamine (described inthe literature: EP 375907 (B1)) (500 mg, 1 mmol) in tetrahydrofuran (3mL). The reaction mixture was heated under microwave irradiation at 110°C. for 15 minutes. The reaction mixture was partitioned between EtOAcand water. The organic phase was dried over magnesium sulphate, filteredand evaporated to dryness. The residue was purified on silica gel byflash column chromatography to afford the title compound as a wax (345mg, 58% yield).

MS (ES⁺) 598.

Step 3:2-((R)-1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-147 and2-((S)-1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-129

A mixture of2-(1-(6-chloropyridin-3-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(157 mg, 0.26 mmol) and N-methylpiperazine (2 mL) was heated undermicrowave irradiation at 180° C. for 40 minutes. The reaction mixturewas partitioned between EtOAc and water. The organic phase was driedover sodium sulphate, filtered and evaporated to dryness. The residuewas purified on silica gel by flash column chromatography to afford thetitle compound as an off-white solid (52 mg, 39% yield).

The two enantiomers were separated using a Berger Minigram SFC system[250×4.6 mm Daicel Chiralcel OD-H column; 4 mLs/min flowrate; co-solventwas 32% Methanol (with 0.25% TEA (Tri-ethyl amine) modifier added);column temperature: 35° C.].

Data for I-147 (first eluted):

¹H NMR (DMSO-d₆, 400 MHz) δ 1.54 (3H, m), 2.00 (3H, m), 2.32-2.37 (4H,m), 3.38 (4H, m), 5.19-5.26 (1H, m), 6.77-6.84 (1H, m), 7.56-7.62 (1H,m), 8.08-8.16 (1H, m), 8.70-8.77 (4H, m), 9.01-9.19 (1H, m), 12.98 (1H,m) mixture of rotamers; MS (ES⁺) 508, (ES⁻) 506.

Data for I-129 (second eluted):

¹H NMR (DMSO-d₆, 400 MHz) δ 1.54 (3H, m), 2.18 (3H, m), 2.33-2.37 (4H,m), 3.38-3.43 (4H, m), 5.18-5.27 (1H, m), 6.77-6.84 (1H, m), 7.56-7.62(1H, m), 8.08-8.16 (1H, m), 8.70-8.77 (4H, m), 9.04-9.18 (1H, m), 12.98(1H, m) mixture of rotamers; MS (ES⁺) 508, (ES⁻) 506.

Example 3N-((1R,4r)-4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methanesulfonamide I-202 andN-((1S,4s)-4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methanesulfonamideI-203

Step 1:2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

DIPEA (7.421 g, 10.00 mL, 57.42 mmol) was added to a suspension of2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(1 g, 1.918 mmol) in acetonitrile (20 mL). The reaction mixture wasstirred for 1 hour then water (5 mL) was added. The mixture was allowedto stir at room temperature for 18 hours. The reaction mixture wasconcentrated in vacuo to give the desired product (880 mg, quantitativeyield).

MS (ES⁺) 460, (ES⁻) 458.

Step 2:2-chloro-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(880.2 mg, 1.916 mmol) was cooled down with an ice bath. Phosphorusoxychloride (2.938 g, 1.786 mL, 19.16 mmol) was added dropwise and thereaction mixture was stirred for 30 minutes at 0° C. and then allowed towarm up to rt and stirred at room temperature for 18 hours. The reactionmixture was quenched by slow addition onto ice. After 1 hour ofstirring, the mixture was extracted into ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to afford a pale orange solid. The solid was triturated further inEtOAc and filtered off (715.4 mg, 78% yield)

MS (ES⁺) 478.

Step 3: (R)-4-(1-aminoethyl)cyclohexanol

A slurry of platinum oxide (285.5 mg, 1.257 mmol) in water (2.9 mL) wasadded to 4-[(1R)-1-Aminoethyl]phenol (5.025 g, 36.63 mmol) in methanol(100 mL). Acetic acid (2.9 mL) was added to the reaction mixture. Thereaction mixture was hydrogenated in a Parr hydrogenator at 60 psi for18 hours. The platinum oxide was filtered off and the mother liquorswere concentrated in vacuo leaving a colourless oil (8.44 g, crude:predominantly product contamined with some (R)-1-cyclohexylethanamineand some starting material).

The crude mixture was dissolved in THF (35 mL) and MeCN (7 mL). NaOH(73.32 mL of 0.5 M, 36.66 mmol) was added followed by di-tert-butyldicarbonate (12.00 g, 54.99 mmol) in portions. The reaction mixture wasallowed to stir at ambient temperature for 18 hours. The reactionmixture was extracted with EtOAc (3 times). The combined organicextracts were washed twice with 1M HCl and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified onsilica gel by flash column chromatography to affordtert-butyl(R)-1-(4-hydroxycyclohexyl)ethylcarbamate as a white solid(4.49 g, 50% yield).

Tert-butyl(R)-1-(4-hydroxycyclohexyl)ethylcarbamate (4.49 g, 18.45 mmol)was dissolved in dichloromethane (25 mL) and cooled to 0° C. undernitrogen. HCl 2M in Ether (27.68 mL of 2 M, 55.35 mmol) was added andthe reaction allowed to warm slowly to ambient temperature for 18 hours.The reaction mixture was concentrated in vacuo. The crude mixture wasdissolved in MeOH (25 mL). MP-Carbonate was added (11.75 g, 36.90 mmol)and the reaction mixture was stirred for 3 hours. The resin was filteredand the mother liquors were concentrated to dryness to afford the titlecompound as an off white solid (2.39 g, 90% yield).

MS (ES⁺) 144.

Step 4:2-((R)-1-(4-hydroxycyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

4-((R)-1-aminoethyl)cyclohexanol (309.4 mg, 2.16 mmol) was dissolved inTHF (10 mL) and DMF (4 mL) and stirred over molecular sieves for 10minutes. Diisopropylethylamine (376.3 μL, 2.160 mmol) was added,followed by2-chloro-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(516.1 mg, 1.080 mmol). The reaction mixture was stirred under nitrogenat ambient temperature for 18 hours. The molecular sieves was removed byfiltration and washed with EtOAc. The filtrate was washed with water,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified on silica gel by flash column chromatography (ISCOCompanion|, 80 g column, 0-100% EtOAc/DCM) to afford the title compoundas a yellow solid (558 mg, 88% yield).

MS (ES⁺) 585, (ES⁻) 583.

Step 5:2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-((R)-1-(4-hydroxycyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(442 mg, 0.7561 mmol) was dissolved in dichloromethane (20 mL) andcooled down to 0° C. Dess-Martin periodinane (384.8 mg, 0.9073 mmol) wasadded and the reaction was allowed to warm up to room temperature. Themixture was stirred for 18 hours. The reaction mixture was partitionedbetween dichloromethane and a 1:1 saturated solution of sodiumhydrosulfite and sodium hydrogen carbonate. The aqueous phase wasfurther extracted with dichloromethane. The combined organic phases weredried over magnesium sulfate, filtered and concentrated to dryness. Theresidue was purified on silica gel by flash column chromatography (ISCOCompanion|, 40 g column, 0-20% EtOAc/DCM) to afford the title compoundas a white solid (411 mg, 93% yield).

MS (ES⁺) 583, (ES⁻) 581.

Step 6:2-((R)-1-(4-aminocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(105 mg, 0.1802 mmol) was dissolved in methanol (5 mL) anddichloromethane (5 mL). Ammonium acetate (138.9 mg, 118.7 μL, 1.802mmol), followed by sodium triacetoxyborohydride (38.19 mg, 0.1802 mmol)were added and the reaction mixture was stirred for 4 hours at roomtemperature. The mixture was partitioned between dichloromethane and asaturated solution of sodium bicarbonate. The aqueous phase wasextracted with dichloromethane. The organic layer was dried overmagnesium sulfate, filtered and concentrated to dryness to afford thedesired product as a yellow solid (95 mg, 90% yield).

MS (ES⁺) 584, (ES⁻) 582.

Step 7:N-((1R,4r)-4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methanesulfonamideI-202 andN-((1S,4s)-4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)methanesulfonamideI-203

2-((R)-1-(4-aminocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(95 mg, 0.1628 mmol) was dissolved in THF (5 mL) anddiisopropylethylamine (25.25 mg, 34.03 μL, 0.1954 mmol) was added. Thereaction mixture was cooled down to 0° C. under nitrogen andmethanesulfonylchloride (15.12 μL, 0.1954 mmol) was added. The reactionmixture was allowed to warm up to ambient temperature and was stirred atthat temperature for 1 hour. An aqueous solution of lithium hydroxide(651.2 μL of 1 M, 0.6512 mmol) was added and the reaction stirred atroom temperature for 3 hours. The mixture was partitioned between ethylacetate and water. The aqueous phase was acidified to pH1 with 1M HCl.The aqueous phase was extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, filtered and concentrated to dryness.The cis and trans isomers were separated by reverse phase preparativeHPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B(solvent A: 0.05% TFA in water; solvent B: CH₃CN) over 16 minutes at 25mL/min] and the resulting fractions were basified by passing themthrough a bicarbonate cartridge. Concentration under vacuo afforded thedesired products (I-202: 12 mg, 27% yield; I-203: 16 mg, 37% yield).

Data for I-202 (first eluted):

¹H NMR (DMSO-d₆, 400 MHz) δ 1.19-1.27 (7H, m), 1.85-1.97 (2H, m),2.06-2.10 (2H, m), 2.91 (3H, s), 3.16-3.22 (1H, m), 4.08-4.17 (2H, m),5.47-5.55 (1H, m), 8.43-8.50 (1H, m), 8.65-8.80 (2H, m), 9.02-9.14 (1H,m), 10.07 (1H, br d); MS (ES⁺) 508, (ES⁻) 506.

Data for I-203 (second eluted):

¹H NMR (DMSO-d₆, 400 MHz) δ 1.39-1.86 (11H, m), 2.97 & 3.00 (3Hrotamers), 3.70-3.74 (1H, m), 4.27-4.32 (1H, s), 4.46-4.58 (1H, m),5.49-5.64 (1H, m), 8.48-8.58 (1H, m), 8.71-8.88 (2H, m), 9.10-9.23 (1H,m), 9.56-10.10 (1H, m); MS (ES⁺) 508, (ES⁻) 506.

Example 42-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-205

Step 1: tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-acetylpiperidine-1-carboxylate (145 g, 0.64mol) and ammonium acetate (225 g, 2.9 mol) in methanol (2 L) was stirredat room temperature for 1.5 hours. Sodium cyanoborohydride (30 g, 0.48mol) was added in one portion and the stirring was continued overnightat room temperature. The reaction mixture was poured in 2N aq. NaOH (2L) and extracted with dichloromethane (2×1 L). The combined extractswere washed with water (1 L), brine (0.3 L), and evaporated to dryness.The residue was dissolved in TBME (1.5 L), dried over sodium sulfate,filtered, and evaporated to dryness under reduced pressure. The residuewas purified by bulb to bulb distillation at 180° C. and 0.1 mbar toafford the title compound as a colorless oil that partly solidified uponstanding (131 g, 90% yield).

¹H NMR (CDCl₃, 300 MHz) δ 4.21-4.08 (2H, m), 2.75-2.58 (3H, m),1.78-1.60 (2H, m), 1.45 (9H, s), 1.44-1.05 (5H, m), 1.04 (3H, d).

Step 2: (R)- and (S)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate

A suspension of tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (40g, 175 mmol) and (S)-(+)-mandelic acid (27 g, 177 mmol) in acetone (400mL) was heated until a clear solution was obtained. The solution wasallowed to cool down to room temperature during 5 hours. The newlyformed precipitate was isolated and rinsed with some acetone (30 mL).The material was recrystallized twice from 300 mL acetone and someethanol (around 25 mL). After drying, 18 g of salt was obtained whichwas treated in an acid base separation, 100 mL dichloromethane and 100mL 1N aq. NaOH. The two layers were separated and the organic layerwashed with 40 mL 1N aq. NaOH and water, dried over sodium sulfate,filtered and concentrated in vacuo to afford (S)-tert-butyl4-(1-aminoethyl)piperidine-1-carboxylate (9.0 g, 99+% ee, 22.5% yield).

From the mother liquor of the above mentioned first crystallizationtert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (20 g, 88 mmol)could be isolated (enriched in the other enantiomer). To the materialwas added (R)-(−)-mandelic acid (14 g, 92 mmol) and acetone (300 mL).The mixture was heated until a clear solution was obtained and allowedto cool to room temperature while stirring. The obtained precipitate wascollected, rinsed with some acetone and recrystallized once as describedabove. After acid base separation, (R)-tert-butyl4-(1-aminoethyl)piperidine-1-carboxylate was obtained (7.5 g, 99+% ee,19% yield).

E.e. was determined as followed: sample (one drop) of the amine and onedrop 1-naphthyl isocyanate in 1 mL dichloromethane was mixed and leftfor 1 day at room temperature (most of the dichloromethane wasevaporated). The sample was concentrated and 5 mL ethanol was added andheated short to 50-60 degrees. 1 mL sample was used. Chiracel OJ-H,eluent Heptane/EtOH/Et₂NH (85/15/0.2), Rf 11.8 and 13.0 min.

Step 3:2-(perfluorophenoxy)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(Methylthio)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(150 mg, 0.31 mmol) was dissolved in dichloromethane at roomtemperature. Meta-chloroperbenzoic acid (110 mg, 0.64 mmol) was added inone portion and the reaction was stirred for 5 minutes.Pentafluorophenol (285 mg, 1.55 mmol) was added and the solution wasstirred at room temperature for 3 hours. The crude mixture was washedwith a diluted solution of sodium bicarbonate and brine. The organicphase was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified on silica gel by flash columnchromatography to afford the title compound as a solid (60 mg, 31%yield).

¹H NMR (CDCl₃, 400 MHz): δ 2.44 (3H, s), 7.38 (2H, d), 8.21 (2H, d),8.47 (1H, s), 8.78 (1H, s), 8.95 (1H, s), 9.32 (1H, s); MS (ES⁺) 626.

Step 4: tert-butyl4-((1R)-1-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)piperidine-1-carboxylate

(R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (43.82 mg, 0.19mmol) was added to a solution of2-(perfluorophenoxy)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(100 mg, 0.16 mmol) and the reaction mixture was stirred at roomtemperature for 2 hours. The crude mixture was concentrated to drynessand the resulting residue was purified on silica gel by flash columnchromatography to afford the title compound (70 mg, 65% yield).

MS (ES⁻) 668.

This intermediate could also be prepared by step 3B and 4B.

Step 3B:5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yldiethyl phosphate.

2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(87% pure, 1.23 g, 2.329 mmol) in dry THF (24.60 mL) was stirred at −25°C. and treated with potassium t-butoxide (2.795 mL of 1.0 M, 2.795 mmol)in THF. The reaction mixture was warmed up to 0° C. for 20 minutes,cooled to −50° C. and treated with diethylchlorophosphate (482.3 mg,403.9 μL, 2.795 mmol). The reaction mixture was stirred at −40° C. for20 minutes and at room temperature for 2 hours. The reaction mixture wasdiluted with ice cold ethyl acetate (60 mL), cooled in ice and shakenquickly with ice cold water containing 1M HCl (2.8 mL, 2.8 mmol),basified with aqueous NaHCO₃ and extracted into ethyl acetate. Theorganic extracts were dried over magnesium sulfate and concentrated togive a pale yellow solid which was triturated with ether and filtered togive a pale yellow solid (810 mg). The mother liquors were concentratedin vacuo and the residue purified on silica gel by flash columnchromatography to afford a colourless solid (219 mg) (total: 1.029 g,74% yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.19-1.28 (6H, m), 2.33 (3H, s), 4.17-4.27(4H, m), 7.51 (2H, d), 8.15 (2H, d), 8.94 (1H, s), 9.24 (1H, s), 9.41(1H, s), 9.48 (1H, s); MS (ES⁺) 596.

Step 4B: tert-butyl4-((1R)-1-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)piperidine-1-carboxylate

5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yldiethyl phosphate (200 mg, 0.3359 mmol) was treated with a solution of(R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (76.70 mg,0.3359 mmol) in THF (2 mL), and diisopropylethylamine (70.22 μL, 0.4031mmol). The reaction mixture was stirred at room temperature for 24hours. The crude mixture was diluted with ethyl acetate and washed withaqueous NaHCO₃. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified on silicagel by flash column chromatography to afford the title compound as acolourless glass (188 mg, 84% yield).

MS (ES⁻) 668.

Step 5:2-((R)-1-(piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile2,2,2-trifluoroacetate

Trifluoroacetic acid (2 mL, 25.96 mmol) was added to a solution oftert-butyl4-((1R)-1-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)piperidine-1-carboxylate(1.2 g, 1.79 mmol) in dichloromethane (25 mL) and the reaction mixturewas stirred at room temperature for 1 hour. The crude mixture wasconcentrated to dryness to give the title compound as a white solid(1.021 g, 98% yield).

MS (ES⁺) 570, (ES⁻) 568.

Step 6:2-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Diisopropylethylamine (179 μl, 1.025 mmol) was added to a mixture of2-((R)-1-(piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile2,2,2-trifluoroacetate (140 mg, 0.205 mmol), TBTU (131.7 mg, 0.14 mmol)and glycolic acid (15.6 mg, 0.205 mmol) in tetrahydrofuran (3 mL). Thereaction mixture was stirred at room temperature for 1 hour. The crudemixture was concentrated to dryness and redissolved in ethyl acetate.The organic phase was washed with a saturated solution of sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified on silica gel by flashcolumn chromatography to afford the title compound (60 mg, 47% yield).Also obtained was 20 mg (21% yield) of the detosylated compound.

MS (ES⁺) 628, (ES⁻) 626.

Step 7:2-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

1M solution of lithium hydroxide (382.5 μl, 0.38 mmol) was added to asolution of2-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(80 mg, 0.128 mmol) in tetrahydrofuran (2 mL). The reaction mixture wasstirred at room temperature for 1 hour. The crude mixture wasconcentrated to dryness and redissolved in ethyl acetate. The organicphase was washed with water, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified on silica gel by flashcolumn chromatography (ISCO Companion|) to afford the title compound asa white solid (30 mg, 50% yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.05-1.2 (5H, m), 1.75-1.95 (5H, m),2.85-2.95 (1H, m), 3.63-3.68 (2H, m), 3.97-4.03 (2H, m), 4.4-4.5 (1H,m), 8.23-8.28 (1H, m), 8.7-8.8 (3H, m), 9.1-9.2 (1H, m), 13.1-13.2 (1H,m); MS (ES⁺) 474, (ES⁺) 472.

Example 5Trans-(2R)—N-(4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)-2-hydroxypropanamideI-265

Step 1: (R)-tert-butyl 1-(4-hydroxycyclohexyl)ethylcarbamate

(R)-tert-butyl 1-(4-hydroxyphenyl)ethylcarbamate (described in theliterature: WO 2007035154 (A1)) (100 mg, 0.4214 mmol) was dissolved inmethanol (5 mL). A methanolic (5 mL) solution of rhodium on alumina (10Wt %, 10 mg) was added. The reaction mixture was place under a hydrogenatmosphere and stir at room temperature for 18 hours. The rhodiumcatalyst was filtered off and the mother liquors were concentrated invacuo. The residue was purified on silica gel by flash columnchromatography to afford the title compound (62 mg, 61% yield).

Data for the cis isomer (26 mg as a white solid):

R_(f) (30% EtOAc/Petrol) 0.40;

¹H NMR (DMSO-d₆, 400 MHz) δ 1.04 (3H, d), 1.19 (1H, m), 1.30-1.40 (6H,m), 1.37 (9H, s), 1.52-1.62 (2H, m), 3.29 (1H, m), 3.73 (1H, br s), 4.21(1H, d), 6.59 (1H, d).

Data for the trans isomer (36 mg as a colourless oil):

R_(f) (30% EtOAc/Petrol) 0.33;

¹H NMR (DMSO-d₆, 400 MHz) δ 0.85-1.21 (5H, m), 1.03 (3H, d), 1.37 (9H,s), 1.60-1.67 (2H, m), 1.78-1.82 (2H, m), 3.20-3.30 (2H, m), 4.41 (1H,br s), 6.62 (1H, d).

Step 2: Cis-(R)-4-(1-(tert-butoxycarbonylamino)ethyl)cyclohexylmethanesulfonate

Cis-(R)-tert-butyl 1-(4-hydroxycyclohexyl)ethylcarbamate (575 mg, 2.363mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. undernitrogen. Triethylamine (478.2 mg, 658.7 μL, 4.726 mmol) followed bymethanesulfonylchloride (284.2 mg, 192.0 μL, 2.481 mmol) were addeddropwise. The reaction mixture was stirred at room temperature for 30minutes. The crude mixture was washed with 1M HCl, water and a saturatedaqueous solution of sodium bicarbonate. The organic extracts were driedover magnesium sulfate, filtered and concentrated in vacuo to give thecompound as a white solid (706 mg, 93% yield).

¹H NMR (CDCl₃, 400 MHz) δ 1.11 (3H, d), 1.38-1.52 (12H, m), 1.54-1.70(4H, m), 2.06-2.20 (2H, m), 3.03 (3H, s), 3.60 (1H, br s), 4.39 (1H, d),5.00 (1H, s).

Step 3: Trans-(R)-tert-butyl 1-(4-aminocyclohexyl)ethylcarbamate

Cis-(R)-4-(1-(tert-butoxycarbonylamino)ethyl)cyclohexyl methanesulfonate(706 mg, 2.196 mmol) was dissolved in DMF (10 mL). Sodium azide (713.8mg, 10.98 mmol) was added and the reaction was heated to 80° C. for 18hours. The reaction mixture was cooled down to ambient temperature andpartitioned between EtOAc (50 mL) and water (50 mL). The organic layerwas separated, dried over magnesium sulfate and filtered. The ethylacetate solution was taken into next step without further manipulation.

The above solution was diluted with MeOH (50 mL) and 10% Pd on carbon(Degussa) (120 mg) was added. The reaction mixture was place under ahydrogen atmosphere and stir at room temperature for 18 hours. Thecatalyst was filtered off and the mother liquors were concentrated invacuo to afford the title compound as an oil (558.4 mg, quantitativeyield).

¹H NMR (CDCl₃, 400 MHz) δ 1.02-1.32 (8H, m), 1.45 (9H, s), 1.62-1.84(4H, m), 1.87-1.95 (2H, m), 2.60 (1H, m), 3.53 (1H, m), 4.39 (1H, m).

Step 4:Trans-tert-butyl(R)-1-(4-((R)-2-hydroxypropanamido)cyclohexyl)ethylcarbamate

Trans-tert-butyl(R)-1-(4-aminocyclohexyl)ethylcarbamate (125 mg, 0.52mmol) was dissolved in DMF (3 mL). D-Lactic Acid (49.52 mg, 0.52 mmol),diisopropylethylamine (166.6 mg, 224.5 μL, 1.29 mmol) and TBTU (165.6mg, 0.5158 mmol) were successively added. The reaction mixture wasallowed to stir at ambient temperature for 3 hours. The crude mixturewas partitioned between ethyl acetate and brine. The organic extractswere dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified on silica gel by column chromatography (ISCOCompanion, 12 g column, 0-10% MeOH/DCM) to afford the title compound(66.1 mg, 41% yield).

¹H NMR (CDCl₃, 400 MHz) δ 1.10 (3H, d), 1.12-1.38 (5H, m), 1.44 (3H, d),1.46 (9H, s), 1.73-1.88 (2H, m), 1.97-2.08 (2H, m), 2.40 (1H, m), 3.58(1H, m), 3.72 (1H, m), 4.22 (1H, q), 4.37 (1H, m), 6.24 (1H, m).

Step 5:Trans-(R)—N-(4-((R)-1-aminoethyl)cyclohexyl)-2-hydroxypropanamide

Trans-tert-butyl(R)-1-(4-((R)-2-hydroxypropanamido)cyclohexyl)ethylcarbamate(66 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL). A solutionof HCl in dioxane (209.9 μL of 4 M, 0.84 mmol) was added. The reactionmixture was stirred at ambient temperature for 18 hours. The crudemixture was concentrated in vacuo and coevaporated three times withdiethylether. The residue was dissolved in methanol (10 mL), passedthrough a sodium bicarbonate cartridge and concentrated in vacuo to givethe desired compound as a white solid (45 mg, quantitative yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 0.80-1.10 (6H, m), 1.12-1.40 (6H, m),1.50-1.82 (5H, m), 2.54 (1H, m), 3.45 (1H, m), 3.91 (1H, quint), 5.40(1H, d), 7.35 (1H, d).

Step 6:Trans-(2R)—N-(4-((1R)-1-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)ethyl)cyclohexyl)-2-hydroxypropanamideI-265

Trans-(R)—N-(4-((R)-1-aminoethyl)cyclohexyl)-2-hydroxypropanamide (45mg, 0.21 mmol) was dissolved in THF (6 mL) and DMF (2 mL) and stirredover 4 Å molecular sieves for 10 minutes.4-(5-(trifluoromethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile(131.9 mg, 0.2100 mmol) was added. The reaction mixture was stirredunder nitrogen at ambient temperature for 18 hours. The molecular sieveswas removed by filtration and washed with EtOAc. The filtrate was washedwith water, dried over magnesium sulfate, filtered and concentrated invacuo. The residue dissolved in tetrahydrofuran (6 mL). Lithiumhydroxide (840.0 μL of 1 M, 0.8400 mmol) was added and the reactionmixture was stirred at room temperature for 18 hours. The crude mixturewas partitioned between ethyl acetate and brine. The organic extractswere dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by reverse phase preparative HPLC [WatersSunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05%TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Thefractions were collected, passed through a sodium bicarbonate cartridgeand freeze-dried to give the title compound as a white solid (19 mg, 18%yield).

¹H NMR (CDCl₃, 400 MHz) δ 1.20-1.35 (8H, m), 1.44 (3H, d), 1.90-2.09(4H, m), 2.34 (1H, d), 3.69-3.81 (1H, m), 4.18-4.28 (2H, m), 5.52(0.33H, d), 5.58 (0.67H, d), 6.27 (1H, d), 8.50 (0.66H, s), 8.58 (0.33H,s), 8.72 (1H, s), 8.77 (0.33H, d), 8.86 (0.67H, d), 9.09 (0.33H, s),9.23 (0.67H, s), 9.64 (1H, br s); MS (ES⁺) 502, (ES⁻) 500.

Example 62-(1-(6-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-266

Step 1:1-methyl-4-(5-(2-methyl-1,3-dioxolan-2-yl)pyridin-2-yl)piperidin-4-ol

2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (500 mg, 2.048 mmol)(described in the literature: Bioorg. Med. Chem., 2005, 13, 6763) wasdissolved in anhydrous tetrahydrofuran (10 mL) and cooled to −78° C.under nitrogen. n-BuLi (901.2 μL of 2.5 M, 2.253 mmol) was addeddropwise and the reaction mixture was stirred at −78° C. for 30 minutes.1-Methyl-4-piperidone (602.6 mg, 655.0 μL, 5.325 mmol) was added and thereaction was allowed to stir at −78° C. for 20 minutes then warmedslowly to ambient temperature. The reaction mixture was stirred at roomtemperature for 18 hours and concentrated in vacuo. The residue waspurified on silica gel by flash column chromatography to afford thetitle compound as a sticky orange solid (483.4 mg, 85% yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.20-1.70 (5H, m), 2.03-2.40 (9H, m), 3.74(2H, t), 4.00 (2H, t), 5.03 (1H, m), 7.65 (1H, d), 7.77 (1H, dd), 8.54(1H, s); MS (ES⁺) 279.

Step 2: 4-(5-(1-aminoethyl)pyridin-2-yl)-1-methylpiperidin-4-ol

1-Methyl-4-(5-(2-methyl-1,3-dioxolan-2-yl)pyridin-2-yl)piperidin-4-ol(483 mg, 1.735 mmol) was suspended in tetrahydrofuran (10 mL). 1M HCl(6.97 mL, 6.97 mmol) was added. The reaction mixture was stirred at roomtemperature for 48 hours and concentrated in vacuo.

The residue was dissolved in MeOH (20 mL). Ammonium acetate (1.337 g,17.35 mmol), acetic acid (1.5 mL, 26.38 mmol) and MP-CNBH₃ (2.871 g,6.947 mmol) were successively added. The reaction mixture was stirred atroom temperature for 18 hours then at 40° C. for a further 7 hours. Thereaction mixture was allowed to cool down to room temperature. The resinwas filtered off and the mother liquors were concentrated in vacuo. Theresidue was dissolved in methanol (20 mL) and MP-Carbonate (2.763 g,8.675 mmol) was added. The reaction mixture was stirred for 6 hours. Theresin was filtered off and the mother liquors were concentrated invacuo. The residue was purified on silica gel by flash columnchromatography to afford the title compound as a yellow solid (159 mg,39% yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.27 (3H, d), 1.44-1.48 (2H, m), 2.08-2.60(9H, m), 4.02 (1H, q), 4.12 (2H, br s), 4.97 (1H, s), 7.58 (1H, d), 7.75(1H, dd), 8.46 (1H, d); MS (ES⁺) 236.

Step 3:2-(1-(6-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrileI-266

2-(Methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(160.2 mg, 0.255 mmol) was added to a solution of4-(5-(1-aminoethyl)pyridin-2-yl)-1-methylpiperidin-4-ol (66.01 mg, 0.28mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred undernitrogen at room temperature for 18 hours. 1M Lithium hydroxide (1.020mL of 1 M, 1.020 mmol) was added and the reaction mixture was stirred atroom temperature for 4 hours. The crude mixture was partitioned betweenethyl acetate and brine. The organic extracts were dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byreverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column,gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH₃CN)over 16 minutes at 25 mL/min] The fractions were collected, passedthrough a sodium bicarbonate cartridge and freeze-dried to give thetitle compound as a white solid (12.5 mg, 9% yield).

¹H NMR (DMSO-d₆, 400 MHz) δ 1.40-1.49 (2H, m), 1.59 (3H, d), 2.05-2.21(2H, m), 2.16 (1.5H, s), 2.16 (1.5H, s), 2.25-2.33 (2H, m), 2.50-2.55(2H, m), 4.96 (1H, d), 5.31-5.41 (1H, m), 7.58-7.65 (1H, m), 7.78-7.87(1H, m), 8.51 (0.5H, s), 8.57 (0.5H, s), 8.70-8.72 (3H, m), 8.52-8.56(1H, m), 8.97 (0.5H, s), 9.20 (0.5H, s), 13.03 (1H, br s); MS (ES⁺) 523,(ES⁺) 521.

Compounds prepared using the methods of Examples 1-6 to give the titlecompounds I-1 to I-299 are shown in Table I.

The characterization data for these compounds is summarized in TableII-A below and includes LC/MS (observed) and ¹H NMR data.

TABLE 1

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-155

I-167

I-103

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

TABLE IIA M + 1 Name (obs) ¹H NMR (DMSO-D₆) Compound No (I-)  22-(methylamino)-4-(5- 319 2.95 (3H, d), 3.02 (3H, d),(trifluoromethyl)-1H- 8.26 (1H, t), 8.44 (1H, t), 8.67 (1H, s),pyrrolo[2,3-b]pyridin-3- 8.72-8.76 (5H, m), 9.24 (2H, d),yl)pyrimidine-5-carbonitrile 13.04 (1H, brs), 13.10 (1H, brs). [~1:1mixture of rotamers]  3 2-(isopropylamino)-4-(5- 347 1.24 (6H, d), 1.29(6H, d), (trifluoromethyl)-1H- 4.19-4.25 (2H, m), 8.26 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.67 (1H, s), 8.71-8.76 (4H, m),yl)pyrimidine-5-carbonitrile 9.17 (2H, d), 13.10 (1H, vbrs). [Mixture ofrotamers]  4 2-(tert-butylamino)-4-(5- 361 1.47 (9H, s), 1.50 (9H, s),(trifluoromethyl)-1H- 8.00 (1H, brs), 8.05 (1H, brs),pyrrolo[2,3-b]pyridin-3- 8.67-8.74 (6H, m), 9.02 (2H, brs),yl)pyrimidine-5-carbonitrile 13.02 (1H, brs), 13.11 (1H, brs). [~1:1mixture of rotamers].  5 2-((S)-1-phenylethylamino)- 409 1.54-1.57 (6H,m), 5.31-5.35 (2H, 4-(5-(trifluoromethyl)-1H- m), 7.17-7.44 (10H, m),pyrrolo[2,3-b]pyridin-3- 8.69-8.71 (4H, m), 8.74 (2H, s), 8.88 (2H,yl)pyrimidine-5-carbonitrile d), 8.97 (1H, s), 9.23 (1H, s), 13.05 (1H,brs), 13.09 (1H, brs). [~1:1 mixture of rotamers]  62-((R)-1-phenylethylamino)- 409 1.54-1.57 (6H, m), 5.31-5.35 (2H,4-(5-(trifluoromethyl)-1H- m), 7.17-7.44 (10H, m),pyrrolo[2,3-b]pyridin-3- 8.69-8.71 (4H, m), 8.74 (2H, s), 8.88 (2H,yl)pyrimidine-5-carbonitrile d), 8.97 (1H, s), 9.23 (1H, s), 13.05 (1H,brs), 13.09 (1H, brs). [~1:1 mixture of rotamers  72-(phenethylamino)-4-(5- 409 2.90-2.97 (4H, m), 3.63-3.65 (2H,(trifluoromethyl)-1H- m), 3.70-3.75 (2H, m), pyrrolo[2,3-b]pyridin-3-7.19-7.31 (10H, m), 8.42 (1H, t), 8.60 (1H, yl)pyrimidine-5-carbonitrilet), 8.68 (1H, s), 8.73-8.77 (5H, m), 9.12 (1H, s), 9.21 (1H, s), 13.05(1H, brs), 13.10 (1H, brs). [~2:3 mixture of rotamers]  82-(benzyl(methyl)amino)-4- 409 3.23 (3H, s), 5.01 (2H, s),(5-(trifluoromethyl)-1H- 5.10 (2H, s), 7.26-7.35 (10H, m),pyrrolo[2,3-b]pyridin-3- 8.65 (1H, s), 8.75-8.79 (5H, m),yl)pyrimidine-5-carbonitrile 8.85 (1H, s), 9.16 (1H, s), 13.09 (2H,brs). [1:1 mixture of rotamers].  9 2-(2-phenylpropan-2- 423 1.77 (12H,s), 7.05-7.07 (1H, m), ylamino)-4-(5- 7.15-7.21 (2H, m), 7.26-7.28 (1H,(trifluoromethyl)-1H- m), 7.27 (4H, m), 8.34 (1H, s),pyrrolo[2,3-b]pyridin-3- 8.49 (1H, s), 8.56 (1H, s),yl)pyrimidine-5-carbonitrile 8.61-8.75 (8H, m), 9.27 (1H, s), 13.00 (1H,brs), 13.03 (1H, brs). [~1:1 mixture of rotamers]  102-(cyclohexylamino)-4-(5- 387 1.25-1.32 (2H, m), 1.33-1.41 (8H,(trifluoromethyl)-1H- m), 1.65 (2H, brd), 1.78 (4H, m),pyrrolo[2,3-b]pyridin-3- 1.95 (4H, m), 3.85-3.95 (2H, m),yl)pyrimidine-5-carbonitrile 8.24 (2H, d), 8.31 (1H, d), 8.64 (2H, s),8.71-8.76 (4H, m), 9.09 (2H, s), 9.12 (1H, s), 13.09 (2H, brs). [~2:1mixture of rotamers]  11 2-(benzyl(ethyl)amino)-4- 423 1.15 (3H, t),1.26 (3H, t), (5-(trifluoromethyl)-1H- 3.70 (2H, q), 3.79 (2H, q), 4.98(2H, pyrrolo[2,3-b]pyridin-3- s), 5.08 (2H, s), 7.27-7.36 (10H,yl)pyrimidine-5-carbonitrile m), 8.63 (1H, s), 8.75-78 (4H, m), 8.80(1H, s), 8.84 (1H, s), 9.11 (1H, s), 13.11 (2H, brs). [~1:1 mixture ofrotamers].  12 2-(4-methoxybenzylamino)- 425 3.68 (3H, s), 3.72 (3H, s),4-(5-(trifluoromethyl)-1H- 4.58 (2H, d), 4.66 (2H, d), 6.85 (2H,pyrrolo[2,3-b]pyridin-3- d), 6.90 (2H, d), 7.25 (2H, d),yl)pyrimidine-5-carbonitrile 7.28 (2H, d), 8.68-8.77 (7H, m), 8.95-8.98(2H, m), 9.25 (1H, s), 13.06 (2H, brs). [~1:1 mixture of rotamers].  132-(3-chlorobenzylamino)-4- 429 4.68 (2H, d), 4.74 (2H, d),(5-(trifluoromethyl)-1H- 7.26-7.41 (8H, m), 8.68 (1H, s),pyrrolo[2,3-b]pyridin-3- 8.71-8.75 (5H, m), 8.83 (2H, s),yl)pyrimidine-5-carbonitrile 9.00 (1H, t), 9.26 (1H, s), 12.13 (2H,vbrs). [~1:1 mixture of rotamers].  14 2-(pyridin-3- 396 4.70 (2H, d),4.76 (2H, d), ylmethylamino)-4-(5- 7.35-7.39 (1H, m), 7.42-7.45 (1H, m),(trifluoromethyl)-1H- 7.77 (1H, d), 7.85 (1H, d),pyrrolo[2,3-b]pyridin-3- 8.45 (1H, d), 8.50 (1H, d), 8.56 (1H,yl)pyrimidine-5-carbonitrile s), 8.63 (1H, s), 8.69 (1H, d), 8.72-8.76(5H, m), 8.88 (2H, m), 9.03 (1H, t), 9.24 (1H, s), 13.07 (1H, s), 13.12(1H, s). [~1:1 mixture of rotamers]  15 2-(2-methoxybenzylamino)- 4253.81 (3H, s), 3.84 (3H, s), 4-(5-(trifluoromethyl)-1H- 4.62 (2H, d),4.69 (2H, d), 6.85 (1H, t), pyrrolo[2,3-b]pyridin-3- 6.91 (1H, t),6.99-7.03 (2H, m), yl)pyrimidine-5-carbonitrile 7.14 (1H, d), 7.21-7.26(3H, m), 8.60 (1H, t), 8.65 (1H, s), 8.70-8.74 (4H, m), 8.81 (1H, s),8.87 (1H, s), 8.88 (1H, t), 9.29 (1H, s), 12.54 (2H, vbrs). [~1:1mixture of rotamers]  16 2-(1-phenylpropylamino)-4- 423 0.85-0.89 (3H,m), 1.76-1.85 (2H, (5-(trifluoromethyl)-1H- m), 4.98-5.06 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.12-7.38 (5H, m), 8.65 (2H, d), 8.70 (1H,yl)pyrimidine-5-carbonitrile d), 8.84 (1H, d), 9.01 (1H, s), 13.04 (1H,s). [~2:1 mixture of rotamers]  17 2-(2-chlorobenzylamino)-4- 429(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  18 2-(3-fluorobenzylamino)-4- 413 4.69(2H, d), 4.75 (2H, d), (5-(trifluoromethyl)-1H- 7.03-7.21 (6H, m),7.31-7.42 (2H, m), pyrrolo[2,3-b]pyridin-3- 8.65 (2H, s), 8.71-8.76 (4H,m), yl)pyrimidine-5-carbonitrile 8.82 (2H, s), 8.99 (1H, t), 9.25 (1H,s), 12.70 (2H, vbrs). [~1:1 mixture of rotamers]  192-(4-chlorobenzylamino)-4- 429 (5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  202-(3-methoxybenzylamino)- 425 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  212-(2-fluorobenzylamino)-4- 413 4.68 (2H, m), 6.57 (1H, s),(5-(trifluoromethyl)-1H- 7.25 (3H, m), 8.50 (1H, s), 8.60 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.80 (2H, m), 9.20 (1H, s)yl)pyrimidine-5-carbonitrile  22 2-(4-fluorobenzylamino)-4- 413(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  23 2-(pyridin-4- 396 ylmethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  24 2-(3-methylbutan-2- 375 0.93 (6H, m),1.17 (3H, m), ylamino)-4-(5- 1.87 (1H, m), 4.00 (1H, m), 8.27 (1H,(trifluoromethyl)-1H- m), 8.70 (3H, m), 9.17 (1H, m)pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  252-(phenylamino)-4-(5- 381 7.14 (1H, t), 7.36 (2H, t),(trifluoromethyl)-1H- 7.69 (2H, d), 8.72 (1H, s), 8.78 (1H, s),pyrrolo[2,3-b]pyridin-3- 8.87 (1H, s), 10.38 (1H, s),yl)pyrimidine-5-carbonitrile 13.15 (1H, brs).  26 2-((R)-1-(4- 440 1.53(3H, d), 3.71 (3H, d), methoxyphenyl)ethylamino)- 5.26 (1H, m), 6.88(2H, m), 7.33 (2H, 4-(5-(trifluoromethyl)-1H- m), 8.70 (3H, m), 8.81(1H, m), pyrrolo[2,3-b]pyridin-3- 8.99 (1H, d), 13.08 (1H, d)yl)pyrimidine-5-carbonitrile  27 2-(2- 421 1.30 (2H, m), 2.17 (H, m),phenylcyclopropylamino)-4- 3.14 (1H, m), 7.17 (5H, m), 8.74 (4H,(5-(trifluoromethyl)-1H- m), 9.34 (1H, d), 13.12 (1H, m)pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  28 tert-butyl4-((5-cyano-4-(5- 502 1.04 (3H, m), 1.38 (9H, s), (trifluoromethyl)-1H-1.72 (4H, m), 2.67 (2H, br s), pyrrolo[2,3-b]pyridin-3- 3.37 (1H, m),3.92 (1H, br s), yl)pyrimidin-2- 8.42 (1H, m), 8.71 (3H, m), 9.20 (1H,ylamino)methyl)piperidine- d), 13.11 (1H, d) 1-carboxylate  292-(cyclohexylmethylamino)- 401 1.10-1.90 (13H, m), 7.37 (1H,4-(5-(trifluoromethyl)-1H- m), 8.52 (1H, m), 8.70 (2H, m),pyrrolo[2,3-b]pyridin-3- 9.20 (1H, d), 13.10 (1H, d)yl)pyrimidine-5-carbonitrile  30 2-((1H-benzo[d]imidazol-2- 435yl)methylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  31 2-((R)-1-(naphthalen-2- 459yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  32 4-(5-(trifluoromethyl)-1H- 464pyrrolo[2,3-b]pyridin-3-yl)- 2-((6- (trifluoromethyl)pyridin-3-yl)methylamino)pyrimidine- 5-carbonitrile  33 2-((R)-1-(4- 487bromophenyl)ethylamino)- 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  34 2-(1,2,3,4-435 tetrahydronaphthalen-1- ylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  352-(pentan-2-ylamino)-4-(5- 375 MeOD/CDCl₃ (400 MHz):(trifluoromethyl)-1H- 1.06 (3H, m), 1.39 (3H, m), 1.49 (2H,pyrrolo[2,3-b]pyridin-3- m), 1.66 (2H, m), 4.29 (1H, m),yl)pyrimidine-5-carbonitrile 7.36 (1H, s), 8.46 (1H, s), 8.61 (1H, s),8.77 (1H, s), 9.26 (1H, s)  36 2-(isobutylamino)-4-(5- 361 MeOD/CDCl₃(400 MHz): (trifluoromethyl)-1H- 1.02 (6H, m), 1.31 (2H, m), 2.04 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.47 (1H, s), 8.62 (1H, s),yl)pyrimidine-5-carbonitrile 8.78 (1H, s), 9.27 (1H, s)  37 2-(3,4- 427MeOD/CDCl₃ (400 MHz): dihydroxybenzylamino)-4- 1.37 (2H, m), 6.74 (3H,m), 6.80 (1H, (5-(trifluoromethyl)-1H- s), 8.48 (1H, s), 8.67 (1H, s),pyrrolo[2,3-b]pyridin-3- 9.23 (1H, s) yl)pyrimidine-5-carbonitrile  382-(2,3-dihydro-1H-inden-1- 421 MeOD/CDCl₃ (400 MHz): ylamino)-4-(5- 1.28(1H, m), 2.01 (1H, m), 2.64 (2H, (trifluoromethyl)-1H- m), 5.71 (1H, m),7.21 (4H, m), pyrrolo[2,3-b]pyridin-3- 8.48 (3H, m), 8.73 (1H, d),yl)pyrimidine-5-carbonitrile 9.19 (1H, s)  39 2-(1-hydroxybutan-2- 377ylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  40 N-(2-(5-cyano-4-(5- 390 MeOD/CDCl₃ (400MHz): (trifluoromethyl)-1H- 1.39 (3H, m), 1.96 (1H, m), 3.19 (1H,pyrrolo[2,3-b]pyridin-3- m), 3.68 (2H, m), 8.51 (1H, s), yl)pyrimidin-2-8.61 (1H, m), 8.80 (1H, m), ylamino)ethyl)acetamide 9.27 (1H, s)  412-(4- 453 MeOD/CDCl₃ (400 MHz): isopropoxybenzylamino)-4- 1.28 (6H, m),1.31 (2H, m), 4.45 (1H, (5-(trifluoromethyl)-1H- m), 6.76 (2H, m), 7.20(2H, m), pyrrolo[2,3-b]pyridin-3- 8.42 (1H, s), 8.49 (1H, m),yl)pyrimidine-5-carbonitrile 8.68 (1H, m), 9.05 (1H, s)  422-(4-hydroxy-3- 441 methoxybenzylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  432-((S)-2-methoxy-1- 439 MeOD/CDCl₃ (400 MHz): phenylethylamino)-4-(5-3.40 (3H, s), 3.78 (2H, m), 5.53 (1H, (trifluoromethyl)-1H- m), 7.31(5H, m), 8.51 (1H, s), pyrrolo[2,3-b]pyridin-3- 8.59 (1H, s), 8.70 (1H,s), yl)pyrimidine-5-carbonitrile 9.04 (1H, s)  44 2-((R)-1-hydroxy-4-405 methylpentan-2-ylamino)-4- (5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  454-(5-(trifluoromethyl)-1H- 477 MeOD/CDCl₃ (400 MHz):pyrrolo[2,3-b]pyridin-3-yl)- 1.67 (3H, m), 5.55 (1H, m), 7.49 (3H,2-((R)-1-(3- m), 8.49 (1H, s), 8.60 (1H, s),(trifluoromethyl)phenyl)ethylamino)pyrimidine- 8.72 (1H, s), 9.05 (1H,s), 5- 9.35 (1H, s) carbonitrile  46 2-(4-phenoxybenzylamino)- 487MeOD/CDCl₃ (400 MHz): 4-(5-(trifluoromethyl)-1H- 4.75 (2H, m), 6.96 (4H,m), 7.20 (5H, pyrrolo[2,3-b]pyridin-3- m), 8.43 (2H, m), 8.49 (1H, s),yl)pyrimidine-5-carbonitrile 8.69 (1H, s), 9.03 (1H, s)  472-((R)-1-hydroxy-3- 391 (Performed at 110° C.) 1.00 (3H,methylbutan-2-ylamino)-4- d), 2.06 (1H, q), 3.67 (1H, m),(5-(trifluoromethyl)-1H- 4.06 (1H, m), 4.25 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.40 (1H, m), 8.60 (1H, s), 8.68 (2H,yl)pyrimidine-5-carbonitrile s), 9.14 (1H, s), 12.64 (1H, br s)  482-(3,5- 431 difluorobenzylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  49 2-((1- 417hydroxycyclohexyl)methylamino)- 4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  502-((6-chloropyridin-3- 430 yl)methylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  512-(1-(pyridin-3- 411 1.57 (3H, d), 5.33 (1H, m), yl)ethylamino)-4-(5-7.47-7.60 (1H, m), 7.94-7.96 (1H, m), (trifluoromethyl)-1H- 8.47-8.86(7H, m), 13.02 (1H, m) pyrrolo[2,3-b]pyridin-3- mixture of rotamersyl)pyrimidine-5-carbonitrile  52 2-(1-(6-methoxypyridin-3- 441 1.57 (3H,d), 3.78-3.82 (3H, d), yl)ethylamino)-4-(5- 5.29 (1H, m), 6.79 (1H, m),(trifluoromethyl)-1H- 7.73-7.79 (1H, m), 8.12-8.21 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.70-8.75 (3H, m), 8.82 (1H, m),yl)pyrimidine-5-carbonitrile 8.97 (1H, m), 13.06 (1H, m) 1:1 mixture ofrotamers  53 2-(3,4- 455 dimethoxybenzylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  54 2-(4-(thiophen-2- 477yl)benzylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  55 2-(4-(1H-1,2,4-triazol-1- 462 4.75 (2H,d), 7.35 (1H, d), yl)benzylamino)-4-(5- 7.41 (1H, d), 7.49 (1H, t), 7.54(1H, t), (trifluoromethyl)-1H- 7.75 (2H, t), 7.87 (2H, s),pyrrolo[2,3-b]pyridin-3- 8.19 (1H, s), 8.22 (1H, s), 8.67 (1H, s),yl)pyrimidine-5-carbonitrile 8.72-8.76 (6H, m), 8.86 (1H, s), 8.92 (1H,t), 9.09 (1H, t), 9.23 (1H, s), 9.27 (1H, s), 9.30 (1H, s), 13.10 (2H,brs). [1:1 mix of rotamers]  56 nzo[d][1,3]dioxol-5- 439 4.56 (2H, d),4.64 (2H, d), ylmethylamino)-4-(5- 6.77-6.89 (5H, m), 6.93 (1H, s),(trifluoromethyl)-1H- 8.71-8.75 (6H, m), 8.80 (1H, t),pyrrolo[2,3-b]pyridin-3- 8.94 (2H, brs), 9.25 (1H, s), 13.07 (2H,yl)pyrimidine-5-carbonitrile vbrs). [1:1 mixture of rotamers]  572-((tetrahydro-2H-pyran-4- 403 1.19-1.27 (2H, m), 1.62-1.68 (2H,yl)methylamino)-4-(5- m), 1.91 (1H, brs), 3.22-3.39 (4H,(trifluoromethyl)-1H- m), 3.83-3.87 (2H, m), 8.43 andpyrrolo[2,3-b]pyridin-3- 8.56 (1H total, 2t), 8.67 (1H, s),yl)pyrimidine-5-carbonitrile 8.71-8.76 (2H, m), 9.15 and 9.21 (1H,total, 2s), 13.03 and 13.12 (1H total, 2brs). [~2:3 mix of rotamers]  582-((S)-1-hydroxy-3- 391 0.92-0.97 (6H, m), 1.91-2.02 (1H,methylbutan-2-ylamino)-4- m), 3.55-3.58 and 3.61-3.70 (2H(5-(trifluoromethyl)-1H- total, 2m), 3.99 (1H, brs), 4.68pyrrolo[2,3-b]pyridin-3- and 4.72 (1H total, 2t), 8.07 andyl)pyrimidine-5-carbonitrile 8.20 (1H total, 2d), 8.66-8.75 (3H, m),9.13 and 9.23 (1H total, 2s), 13.05 (1H, brs).  59 2-(4- 438 MeOD/CDCl₃1.26 (2H, s), (dimethylamino)benzylamino)- 3.09 (6H, s), 7.18 (2H, d),7.45 (2H, 4-(5-(trifluoromethyl)- d), 8.56 (2H, m), 8.78 (1H, s),1H-pyrrolo[2,3-b]pyridin-3- 9.01 (1H, s) yl)pyrimidine-5-carbonitrile 60 2-(2,5- 423 MeOD/CDCl₃ 2.24 (3H, s), dimethylbenzylamino)-4-(5- 2.28(2H, s), 2.33 (3H, s), 7.08 (3H, (trifluoromethyl)-1H- m), 8.57 (2H, m),8.76 (1H, s), pyrrolo[2,3-b]pyridin-3- 9.07 (1H, s)yl)pyrimidine-5-carbonitrile  61 2-((R)-1- 415 (CDCl₃) 1.30 (8H, m),4.18 (7H, cyclohexylethylamino)-4- m), 4.18 (1H, m), 7.54 (1H, s),(5-(trifluoromethyl)-1H- 8.47 (1H, s), 8.69 (1H, s),pyrrolo[2,3-b]pyridin-3- 9.01 (1H, s), 9.34 (1H, s)yl)pyrimidine-5-carbonitrile  62 2-((2,3-dihydrobenzofuran- 4375-yl)methylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  63 2-(1-methylpiperidin-4- 402ylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  64 2-(pyridin-2- 396 4.80 (2H, m), 7.33(2H, m), ylmethylamino)-4-(5- 7.73 (1H, m), 8.51 (1H, d), 8.70 (4H,(trifluoromethyl)-1H- m), 9.09 (1H, d) pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  65 2-((1R,2R)- 399 bicyclo[2.2.1]heptan-2-ylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  66 2-(ethylamino)-4-(5- 333(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  67 2-((1-ethylpyrrolidin-2- 416yl)methylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  68 2-(2-(piperidin-2- 416yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  69 2-(2- 418 morpholinoethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  70 2-(3- 432 morpholinopropylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  71 2-(cyanomethylamino)-4-(5- 4.49-4.53(2H, m), 8.76-8.85 (3H, (trifluoromethyl)-1H- m), 8.92 (0.5H, s), 9.00(0.5H, t), pyrrolo[2,3-b]pyridin-3- 9.23 (1H, s), 13.14 (0.5H, brs),yl)pyrimidine-5-carbonitrile 13.18 (0.5H, brs).  72 N-(4-((5-cyano-4-(5-2.00 (3H, d), 4.60 (1H, d), (trifluoromethyl)-1H- 4.68 (1H, d), 7.25(2H, dd), 7.51 (2H, pyrrolo[2,3-b]pyridin-3- dd), 8.71-8.74 (3H, m),yl)pyrimidin-2- 8.80-8.82 (0.5H, m), 8.97-8.99 (1H, m),ylamino)methyl)phenyl)acetamide 9.26 (0.5H, s), 9.87 (0.5H, s), 9.92(0.5H, s), 13.06 (0.5H, brs), 13.09 (0.5H, brs).  732-(cyclopentylamino)-4-(5- 1.59-1.65 (4H, m), 1.66-1.74 (2H,(trifluoromethyl)-1H- m), 1.99-2.08 (2H, m), pyrrolo[2,3-b]pyridin-3-4.30-4.39 (1H, m), 8.38-8.41 (1H, m), yl)pyrimidine-5-carbonitrile8.66-8.75 (3H, m), 9.18 and 9.20 (1H total, 2s), 13.03 and 13.09 (1Htotal, 2s).  74 2-(tetrahydro-2H-pyran-4- 1.38-1.45 (2H, m), 1.63-1.70(2H, ylamino)-4-(5- m), 3.15-3.21 (2H, partly (trifluoromethyl)-1H-obscured m), 3.69-3.74 (2H, m), pyrrolo[2,3-b]pyridin-3- 3.89-3.94 (1H,m), 8.14-8.18 (1H, yl)pyrimidine-5-carbonitrile m), 8.46-8.54 (3H, m),8.85 and 8.95 (1H total, 2s), 12.81 and 12.89 (1H total, 2brs).  752-(2-hydroxy-1- 3.69-3.78 (2H, m), 5.04-5.09 (1H,phenylethylamino)-4-(5- m), 5.22-5.27 (1H, m), (trifluoromethyl)-1H-7.19-7.44 (5H, m), 8.68-8.82 (4H, m), pyrrolo[2,3-b]pyridin-3- 8.97(0.5H, s), 9.25 (0.5H, s), 13.06 yl)pyrimidine-5-carbonitrile and 13.09(1H total, 2brs).  76 2-(cyclopropylamino)-4-(5- 0.63-0.69 (2H, m),0.78-0.87 (2H, (trifluoromethyl)-1H- m), 2.85-2.88 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.53-8.79 (4H, m), 9.18 and 9.46 (1H total,yl)pyrimidine-5-carbonitrile 2s), 13.01 (1H, vbrs).  772-(sec-butylamino)-4-(5- 0.85-0.91 (3H, m), 1.22-1.26 (3H,(trifluoromethyl)-1H- m), 1.54-1.69 (2H, m), pyrrolo[2,3-b]pyridin-3-4.03-4.08 (1H, m), 8.23-8.27 (1H, m), yl)pyrimidine-5-carbonitrile8.66-8.75 (3H, m), 9.14 and 9.18 (1H total, 2s), 13.03 and 13.09 (1Htotal, 2s).  78 2-((S)-tetrahydrofuran-3- 2.25-2.29 (1H, m), 2.33-2.38(1H, ylamino)-4-(5- m), 3.67-3.88 (2H, m), (trifluoromethyl)-1H-3.89-3.96 (2H, m), 4.57-4.59 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.57-8.63(1H, m), 8.71-8.76 (3H, m), yl)pyrimidine-5-carbonitrile 9.11 (0.5H, s),9.20 (0.5H, s), 13.07 (1H, brs).  79 2-(prop-2-ynylamino)-4-(5- 3.11 and3.19 (1H total, 2s), (trifluoromethyl)-1H- 4.21 (2H, m), 8.68-8.91 (4H,m), 9.26 pyrrolo[2,3-b]pyridin-3- and 9.36 (1H total, 2s), 13.08 andyl)pyrimidine-5-carbonitrile 13.12 (1H total, 2brs).  802-(3-(1H-imidazol-1- 2.15-2.24 (2H, m), 4.27-4.31 (2H,yl)propylamino)-4-(5- m), 7.64 (0.5H, s), 7.70 (0.5H, s),(trifluoromethyl)-1H- 7.83 (1H, d), 8.43 (0.5H, t),pyrrolo[2,3-b]pyridin-3- 8.51 (0.5H, t), 8.72-8.76 (3H, m),yl)pyrimidine-5-carbonitrile 9.05 (0.5H, s), 9.10 (0.5H, s). 9.14 (0.5H,s), 9.19 (0.5H, s), 13.08 (0.5H, s), 13.13 (0.5H, s), 14.25 (1H, vbrs). 81 2-(((1S,3R)-3- 1.20-1.35 (1H, m), 1.40-1.55 (2H,hydroxycyclopentyl)methylamino)- m), 1.82-1.91 (3H, m), 4-(5- 3.31-3.47(2H, partly obscured m), (trifluoromethyl)-1H- 4.13 (1H, m), 4.38-4.40(1H, m), 8.44 pyrrolo[2,3-b]pyridin-3- and 8.54 (1H total, 2t),yl)pyrimidine-5-carbonitrile 8.66-8.74 (3H, m), 9.17 and 9.20 (1H total,2s), 13.03 and 13.11 (1H total, 2brs).  82 2-(1-methoxypropan-2-1.21-1.25 (3H, m), 3.25 (3H, d), ylamino)-4-(5- 3.36-3.51 (2H, partlyobscured (trifluoromethyl)-1H- m), 4.33-4.39 (1H, m), 8.23 andpyrrolo[2,3-b]pyridin-3- 8.32 (1H total, 2d),yl)pyrimidine-5-carbonitrile 8.68-8.75 (3H, m), 9.13 and 9.20 (1H total,2s), 13.09 (1H, brs).  83 2-(sec-butylamino)-4-(5- 0.85-0.91 (3H, m),1.22-1.26 (3H, (trifluoromethyl)-1H- m), 1.54-1.69 (2H, m),pyrrolo[2,3-b]pyridin-3- 4.03-4.08 (1H, m), 8.23-8.27 (1H, m),yl)pyrimidine-5-carbonitrile 8.66-8.75 (3H, m), 9.14 and 9.18 (1H total,2s), 13.03 and 13.09 (1H total, 2s).  84 2-(1-(3-chloro-4- 474 1.54 (3H,d), 3.82 masked signal, methoxyphenyl)ethylamino)- 5.25 (1H, m),7.04-7.47 (3H, m), 4-(5-(trifluoromethyl)-1H- 8.70-8.80 (4H, m),8.97-9.20 (1H, pyrrolo[2,3-b]pyridin-3- m), 13.05 (1H, m) 1:1 mixture ofyl)pyrimidine-5-carbonitrile rotamers  85 2-(2-(pyrrolidin-2- 402yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  86 2-(2- 434 thiomorpholinoethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  87 2-((R)-2- 388(aminomethyl)pyrrolidin-1- yl)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  882-((R)-pyrrolidin-2- 388 ylmethylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  892-((1-benzylpiperidin-4- 492 yl)methylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  904-(5-(1,1-Trifluoromethyl)- 411 1H-pyrrolo[2,3-b]pyridin-3- yl)-2-(4-hydroxybenzylamino)pyrimidine- 5-carbonitrile  912-(2-hydroxypropylamino)- 363 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  922-(4-(1H-pyrazol-1- 461 yl)benzylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  932-(propylamino)-4-(5- 347 (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  94 2-(3-chloro-4- 459methoxybenzylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  95 2-(4- 403 hydroxycyclohexylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  96 2-(2-hydroxybutylamino)-4- 377(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  97 2-((R)-2- 363 hydroxypropylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile  98 2-((2R,3S)-1,3- 393dihydroxybutan-2-ylamino)- 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile  99 2-((R)-1-(4-425 1.51 (3H, m), 5.23 (1H, m), hydroxyphenyl)ethylamino)- 6.65-6.73(2H, m), 6.96-7.18 (1H, m), 4-(5-(trifluoromethyl)-1H- 7.18-7.23 (2H,m), 8.69-8.79 (4H, pyrrolo[2,3-b]pyridin-3- m), 9.02-9.21 (1H, m), 9.27(1H, yl)pyrimidine-5-carbonitrile m), 13.04 (1H, m) mixture of rotamers100 2-(1-(6-oxo-1,6- 426 1.51 (3H, m), 5.10 (1H, m), dihydropyridin-3-6.33 (1H, m), 6.96-7.22 (2H, m), yl)ethylamino)-4-(5- 7.51 (1H, m),8.66-8.74 (4H, m), (trifluoromethyl)-1H- 8.98-9.18 (1H, m), 11.46 (1H,s), pyrrolo[2,3-b]pyridin-3- 13.06 (1H, m) mixture of rotamersyl)pyrimidine-5-carbonitrile 101 2-(1-(1-acetylpiperidin-4- 4581.15-1.23 (5H, m), 1.76 (3H, m), yl)ethylamino)-4-(5- 1.93-1.98 (3H, m),2.96 (1H, m), (trifluoromethyl)-1H- 3.80 (1H, m), 4.04 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.41 (1H, m), 8.30 (1H, m),yl)pyrimidine-5-carbonitrile 8.67-8.75 (3H, m), 9.10 (1H, m), 13.10 (1H,m) mixture of rotamers 102 2-(1-(4-(4-methylpiperazin- 507 1.51 (3H, m),2.82-2.89 (5H, m), 1-yl)phenyl)ethylamino)-4- 3.09 (2H, m), 3.43 (2H,m), (5-(trifluoromethyl)-1H- 3.78 (2H, m), 5.26 (1H, m),pyrrolo[2,3-b]pyridin-3- 6.92-6.99 (2H, m), 7.28-7.33 (2H, m),yl)pyrimidine-5-carbonitrile 8.70 (2H, m), 8.80 (1H, m), 9.03-9.21 (1H,m), 9.57 (1H, m), 13.10 (1H, m) mixture of rotamers 1032-((R)-1-hydroxy-3- 366 0.95-0.97 (6H, m), 1.97-2.03 (1H,methylbutan-2-ylamino)-4- m), 3.55-3.61 (2H, m), 3.94 (1H,(5-(trifluoromethyl)-1H- m), 4.60 (1H, m), 6.75 (1H, vbrs),pyrrolo[2,3-b]pyridin-3- 7.09 (1H, d), 8.20 (1H, d),yl)pyrimidine-5-carbonitrile 8.62 (1H, s), 8.66 (1H, s), 9.20 (1H, brs),12.75 (1H, s). 104 2-(2-hydroxy-1- 419 (tetrahydrofuran-3-yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 105 2-(2-hydroxy-1-(tetrahydro- 4332H-pyran-4-yl)ethylamino)- 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1062-(1-cyclopropyl-3- 403 hydroxypropylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1072-((R)-1-hydroxypropan-2- 363 ylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1082-((2R,3S)-1,3- 393 dihydroxybutan-2-ylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 109 2-(2-hydroxyethylamino)-4- 349(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 110 2-(1-methoxy-3- 405methylbutan-2-ylamino)-4- (5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1112-((S)-1-hydroxy-3,3- 405 dimethylbutan-2-ylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 112 2-(1-(4- 453 (DMSO) 1.28 (3H, q), 1.52(1H, ethoxyphenyl)ethylamino)- d), 3.98 (2H, m), 5.26 (1H, m),4-(5-(trifluoromethyl)-1H- 6.82-6.90 (2H, m), 7.28-7.34 (2H,pyrrolo[2,3-b]pyridin-3- m), 8.70-8.81 (4H, m),yl)pyrimidine-5-carbonitrile 9.01-9.22 (1H, m), 13.05 (1H, m) 1:1mixture of rotamers 113 2-(2-hydroxy-1-(pyridin-3- 426 (DMSO) 3.80masked signal, yl)ethylamino)-4-(5- 5.30 (1H, m), 7.49-7.63 (1H, m),(trifluoromethyl)-1H- 7.98-8.14 (1H, m), 8.52-9.24 (8H, m),pyrrolo[2,3-b]pyridin-3- 13.09 (1H, m) 1:1 mixture ofyl)pyrimidine-5-carbonitrile rotamers 114 2-((S)-2,3- 379dihydroxypropylamino)-4- (5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 115 2-((R)-2,3-379 dihydroxypropylamino)-4- (5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1162-((2S,3R)-1-hydroxy-3- 405 methylpentan-2-ylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 117 2-((1-methylpiperidin-4- 416yl)methylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 118 2-((1-ethylpiperidin-4- 430yl)methylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 119 2-((1R,3S)-3- 403 CDCl₃/MeOD 1.40-2.40(9H, m), (hydroxymethyl)cyclopentyl 4.51 (1H, m), 8.44 (1H, s),amino)-4-(5- 8.52 (1H, d), 8.60 (1H, s), 9.26 (1H, m)(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 120 2-((1H-pyrrolo[2,3- 435 CDCl₃/MeOD:2.04 (2H, s), b]pyridin-5- 2.66 (1H, s), 6.70 (1H, d), 7.55 (1H, d),yl)methylamino)-4-(5- 8.58 (3H, m), 8.90 (1H, s), (trifluoromethyl)-1H-9.35 (1H, s) pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 121N-(4-(1-(5-cyano-4-(5- 466 CDCl₃/MeOD: 1.63 (3H, m),(trifluoromethyl)-1H- 2.09 (3H, d), 5.39 (1H, m), 7.39 (2H,pyrrolo[2,3-b]pyridin-3- d), 7.49 (2H, d), 8.56 (1H, d), yl)pyrimidin-2-8.65 (1H, s), 8.78 (1H, s), 9.14 (1H, s), ylamino)ethyl)phenyl)acetamide9.40 (1H, s), 9.85 (1H, m) 122 2-(1-(3-chloro-4- 459 CDCl₃: 1.68 (3H,s), 5.32 (1H, hydroxyphenyl)ethylamino)- m), 6.13 (1H, br s), 7.00 (1H,m), 4-(5-(trifluoromethyl)-1H- 7.22 (2H, m), 7.40 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.54 (1H, d), 8.69 (1H, s), 8.84 (1H, d),yl)pyrimidine-5-carbonitrile 9.11 (1H, s), 10.06 (1H, s) 123 tert-butyl4-(4-(1-(5-cyano- 593 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-2-ylamino)ethyl)phenyl)piperazine- 1-carboxylate 124 2-(1-(4-(piperazin-1-493 1.52 (3H, s), 3.24 (8H, m), yl)phenyl)ethylamino)-4-(5- 5.30 (1H,m), 6.96 (2H, m), 7.29 (2H, (trifluoromethyl)-1H- m), 8.71 (6H, m), 9.21(1H, d), pyrrolo[2,3-b]pyridin-3- 13.08 (1H, m)yl)pyrimidine-5-carbonitrile 125 2-(1-(4- 494 1.53 (3H, s), 3.03 (4H,m), morpholinophenyl)ethylamino)- 3.69 (4H, m), 5.26 (1H, m), 6.90 (2H,4-(5-(trifluoromethyl)- m), 7.26 (2H, m), 8.74 (4H, m),1H-pyrrolo[2,3-b]pyridin-3- 9.21 (1H, d), 13.06 (1H, m)yl)pyrimidine-5-carbonitrile 126 2-(1-(4-(4-methyl-1,4- 521 1.63 (3H,d), 2.01 (2H, m), diazepan-1- 2.35 (3H, s), 2.59 (2H, m),yl)phenyl)ethylamino)-4-(5- 2.72 (2H, m), 3.44 (2H, m), 3.54 (2H,(trifluoromethyl)-1H- m), 5.33 (1H, d), 6.64 (2H, d),pyrrolo[2,3-b]pyridin-3- 7.24 (2H, d), 8.45 (1H, s),yl)pyrimidine-5-carbonitrile 8.59 (1H, s), 8.67 (1H, s), 9.19 (1H, s)127 2-((R)-1-(4-(4- 507 1.53 (3H, d), 2.20-2.25 (3H, m),methylpiperazin-1- 2.4-2.5 (4H, m), 3.02-3.08 (4H, m),yl)phenyl)ethylamino)-4-(5- 5.2-5.3 (1H, m), 6.83-6.9 (2H, m),(trifluoromethyl)-1H- 7.23-7.28 (2H, m), pyrrolo[2,3-b]pyridin-3-8.68-8.8 (4H, m), 9.1 (0.6H, s), yl)pyrimidine-5-carbonitrile 9.25(0.4H, s), 13.2 (1H, s) 128 2-((R)-3-methyl-1- 460 (at 110° C.) 0.99(6H, m), morpholinobutan-2- 2.33-2.51 (6H, m), 3.47 (4H, br m),ylamino)-4-(5- 4.27 (1H, m), 7.56 (1H, m), (trifluoromethyl)-1H- 8.61(1H, s), 8.70 (2H, s), 9.12 (1H, pyrrolo[2,3-b]pyridin-3- s), 12.66 (1H,br s) yl)pyrimidine-5-carbonitrile 129 2-((S)-1-(6-(4- 508 ¹H NMR(DMSO-d₆, 400 MHz) δ methylpiperazin-1- 1.54 (3H, m), 2.18 (3H, m),yl)pyridin-3-yl)ethylamino)- 2.33-2.37 (4H, m), 3.38-3.43 (4H, m),4-(5-(trifluoromethyl)-1H- 5.18-5.27 (1H, m), 6.77-6.84 (1H,pyrrolo[2,3-b]pyridin-3- m), 7.56-7.62 (1H, m),yl)pyrimidine-5-carbonitrile 8.08-8.16 (1H, m), 8.70-8.77 (4H, m),9.04-9.18 (1H, m), 12.98 (1H, m) mixture of rotamers 130 2-((R)-1-(4-(4-583 CDCl³: 1.70 (3H, m), 2.61 (4H, benzylpiperazin-1- s), 3.20 (4H, s),3.58 (2H, s), yl)phenyl)ethylamino)-4-(5- 3.80 (1H, m), 6.31 (1H, m),6.92 (2H, (trifluoromethyl)-1H- m), 7.34 (7H, m), 8.59 (1H, d),pyrrolo[2,3-b]pyridin-3- 8.75 (1H, s), 8.86 (1H, d),yl)pyrimidine-5-carbonitrile 9.24 (1H, d) 131 2-(1-(4-(1,4-diazepan-1-507 yl)phenyl)ethylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 1322-((R)-1-morpholinopropan- 432 (at 110° C.) 1.30 (3H, d),2-ylamino)-4-(5- 2.50-2.67 (6H, m), 3.55 (4H, m), (trifluoromethyl)-1H-4.39 (1H, m), 7.63 (1H m), pyrrolo[2,3-b]pyridin-3- 8.62 (1H, s), 8.69(2H, s), 9.11 (1H, yl)pyrimidine-5-carbonitrile s), 12.66 (1H, br s) 1332-((R)-1-(4- 452 1.51 (3H, m), 2.81 (6H, m),(dimethylamino)phenyl)ethylamino)- 5.23 (1H, m), 6.63-6.71 (2H, m),4-(5- 7.20-7.25 (2H, m), 8.70 (4H, m), (trifluoromethyl)-1H- 9.07-9.22(1H, m), 13.07 (1H, m) pyrrolo[2,3-b]pyridin-3- mixture of rotamersyl)pyrimidine-5-carbonitrile 134 2-((R)-1-(1-acetylpiperidin- 458 1.03(1H, m), 1.19-1.23 (4H, m), 4-yl)ethylamino)-4-(5- 1.76-1.84 (3H, m),1.93-1.98 (3H, (trifluoromethyl)-1H- m), 2.96 (1H, m), 3.80 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.07 (1H, m), 4.41 (1H, m),yl)pyrimidine-5-carbonitrile 8.10 (1H, m), 8.57-8.65 (2H, m), 8.81 (1H,m), 9.12 (1H, m), 13.10 (1H, m) mixture of rotamers 1352-((S)-1-(1-acetylpiperidin- 458 1.02 (1H, m), 1.21 (4H, m),4-yl)ethylamino)-4-(5- 1.76-1.84 (3H, m), 1.93-1.96 (3H, m),(trifluoromethyl)-1H- 2.96 (1H, m), 3.80 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.05 (1H, m), 4.41 (1H, m), 8.14 (1H,yl)pyrimidine-5-carbonitrile m), 8.58-8.79 (3H, m), 9.12 (1H, m), 13.10(1H, m) mixture of rotamers 136 N-(4-((1R)-1-(5-cyano-4-(5- 502 1.54(3H, m), 2.91 (3H, m), (trifluoromethyl)-1H- 5.29 (1H, m), 7.12-7.19(2H, m), pyrrolo[2,3-b]pyridin-3- 7.34-7.40 (2H, m), 8.69-8.74 (3H, m),yl)pyrimidin-2- 8.82 (1H, m), 8.97-9.21 (1H, m),ylamino)ethyl)phenyl)methanesulfonamide 9.66 (1H, m), 13.06 (1H, m)mixture of rotamers 137 N-(4-((1R)-1-(5-cyano-4-(5- 492 0.75 (4H, m),1.54 (3H, m), (trifluoromethyl)-1H- 1.74 (1H, m), 5.26 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.29-7.35 (2H, m), 7.48-7.55 (2H, m),yl)pyrimidin-2- 8.69-8.74 (3H, m), 8.80 (1H, m),ylamino)ethyl)phenyl)cyclo 9.00-9.22 (1H, m), 10.14 (1H, m),propanecarboxamide 13.07 (1H, m) mixture of rotamers 1382-(1-(6-morpholinopyridin- 495 1.55 (3H, d), 3.38-3.42 (2H, m),3-yl)ethylamino)-4-(5- 3.63-3.69 (4H, m), 5.20-5.27 (1H,(trifluoromethyl)-1H- m), 6.78-6.85 (1H, m), pyrrolo[2,3-b]pyridin-3-7.59-7.65 (1H, m), 8.11 (0.5H, s), yl)pyrimidine-5-carbonitrile 8.19(0.5H, s), 8.71-8.77 (4H, m), 9.05 (0.5H, s), 9.19 (0.5H, s), 13.03(0.5H, s), 13.09 (0.5H, s). ~1:1 mixture of rotamers, water peakobscures some signals 139 2-(1-(6-(4-methylpiperazin- 508 1.54 (3H, d),2.17 (1.5H, s), 1-yl)pyridin-3- 2.20 (1.5H, s), 2.33-2.37 (4H, m),yl)ethylamino)-4-(5- 3.37-3.43 (4H, m), 5.20-5.24 (1H, m),(trifluoromethyl)-1H- 6.77-6.83 (1H, m), 7.57-7.62 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.08 (0.5H, s), 8.16 (0.5H, s),yl)pyrimidine-5-carbonitrile 8.69-8.73 (4H, m), 9.05 (0.5H, s), 9.18(0.5H, s), 12.95 (1H, vbrs). ~ 1:1 mixture of rotamers 1402-((R)-1-(4-(4- 535 isopropylpiperazin-1- yl)phenyl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 141 methyl 4-((1R)-1-(5-cyano- 482 1.53(3H, m), 3.62 (3H, m), 4-(5-(trifluoromethyl)-1H- 5.28 (1H, m),7.28-7.41 (4H, m), pyrrolo[2,3-b]pyridin-3- 8.69-8.78 (4H, m), 8.99-9.21(1H, m), yl)pyrimidin-2- 9.58 (1H, m), 13.03 (1H, br s)ylamino)ethyl)phenylcarbamate mixture of rotamers 1422-((R)-1-(3-fluoro-4-(4- 525 CDCl3 1.55 (3H, d), methylpiperazin-1-2.17-2.24 (3H, m), 2.4-2.5 (4H, m), yl)phenyl)ethylamino)-4-(5-2.95-3.02 (4H, m), 5.22-5.28 (1H, m), (trifluoromethyl)-1H- 6.95-7.02(1H, m), 7.02-7.18 (2H, m), pyrrolo[2,3-b]pyridin-3- 8.7-8.8 (3H, m),8.97 (0.5H, s), yl)pyrimidine-5-carbonitrile 9.12 (0.5H, s), 13.1 (1H,brs) 143 2-(1-(6- 453 1.54 (3H, d), 2.94 (3H, s),(dimethylamino)pyridin-3- 2.98 (3H, s), 5.18-5.26 (1H, m),yl)ethylamino)-4-(5- 6.61 (1H, dd), 7.54-7.59 (1H, m),(trifluoromethyl)-1H- 8.05 (0.5H, s), 8.13 (0.5H, s),pyrrolo[2,3-b]pyridin-3- 8.70-8.75 (4H, m), 9.07 (0.5H, s),yl)pyrimidine-5-carbonitrile 9.19 (0.5H, s), 13.02 (0.5H, brs), 13.09(0.5H, brs). ~1:1 mixture of rotamers 144 N-(4-((1R)-1-(5-cyano-4-(5-480 1.05 (3H, m), 1.54 (3H, m), (trifluoromethyl)-1H- 2.25-2.30 (2H, m),5.26 (1H, m), pyrrolo[2,3-b]pyridin-3- 7.21-7.35 (2H, m), 7.48-7.55 (2H,m), yl)pyrimidin-2- 8.69-8.74 (3H, m), 8.78 (1H, m),ylamino)ethyl)phenyl)propionamide. 9.00-9.22 (1H, m), 9.78 (1H, m),13.03 (1H, m) mixture of rotamers 145 2-((R)-1-(4-(2- 492 1.54 (3H, m),1.99-2.06 (2H, m), oxopyrrolidin-1- 3.74-3.82 (3H, m), 5.29 (1H, m),yl)phenyl)ethylamino)-4-(5- 7.36-7.42 (2H, m), 7.54-7.61 (2H,(trifluoromethyl)-1H- m), 8.67-8.71 (3H, m), 8.78 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.99-9.21 (1H, m). Mixture ofyl)pyrimidine-5-carbonitrile rotamers 146 2-((R)-1-(4-((S)-1- 508 MeOD1.59 (3H, m), 2.34 (2H, methylpyrrolidin-3- m), 2.96 (3H, m), 3.32 (3H,m), yloxy)phenyl)ethylamino)- 3.82 (2H, m), 5.25 (2H, m),4-(5-(trifluoromethyl)-1H- 6.90 (2H, d), 7.39 (2H, d), 8.45 (1H, s),pyrrolo[2,3-b]pyridin-3- 8.60 (1H, s), 8.71 (1H, s),yl)pyrimidine-5-carbonitrile 9.04 (1H, d) 147 2-((R)-1-(6-(4- 508methylpiperazin-1- yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile Compound No I- 149 2-((R)-1-(2-fluoro-4-(4-525 1.48-1.52 (3H, m), .212 (3H, s), methylpiperazin-1- 2.7-2.76 (2H,m), 2.9-3.03 (2H, yl)phenyl)ethylamino)-4-(5- m), 3.07-3.2 (2H, m),3.8-3.9 (2H, (trifluoromethyl)-1H- m), 5.4-5.5 (0.4H, m),pyrrolo[2,3-b]pyridin-3- 5.53-5.6 (0.6H, m), 6.7-6.85 (2H, m),yl)pyrimidine-5-carbonitrile 7.3-7.4 (1H, m), 8.7-8.9 (4H, m), 8.97(0.6H, s), 9.22 (0.4H, s), 9.63 (1H, br s), 13.0-13.15 (1H, m) 1502-(1-(1- 494 1.2-1.35 (5H, m), 1.5-1.62 (1H,(methylsulfonyl)piperidin-4- m), 1.8-1.97 (2H, m), yl)ethylamino)-4-(5-2.6-2.74 (2H, m), 2.82-2.87 (3H, m), (trifluoromethyl)-1H- 3.5-3.65 (2H,m), 4.0-4.1 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.3-8.36 (1H, m), 8.67-8.8(3H, yl)pyrimidine-5-carbonitrile m), 9.1-9.2 (1H, m), 13.0-13.15 (1H,m) 151 2-(1-(6- 439 1.55 (3H, d), 2.85 (1.5H, brs),(methylamino)pyridin-3- 2.89 (1.5H, brs), 5.17-5.22 (1H,yl)ethylamino)-4-(5- m), 6.99 (1H, vbrs), 7.73 (0.5H,(trifluoromethyl)-1H- brs), 7.87 (1H, s), 7.96 (0.5H, m),pyrrolo[2,3-b]pyridin-3- 8.72-8.79 (4H, m), 8.91 (0.5H, s),yl)pyrimidine-5-carbonitrile 9.18 (0.5H, s), 13.08 (0.5H, s), 13.12(0.5H, s); ~1:1 mixture of rotamers 152 methyl 4-(1-(5-cyano-4-(5- 4741.0-1.3 (6H, m), 1.68-1.72 (4H, (trifluoromethyl)-1H- m), 2.65-2.85 (2H,m), pyrrolo[2,3-b]pyridin-3- 3.52-3.58 (3H, m), 3.9-4.1 (3H, m),yl)pyrimidin-2- 8.25-8.29 (1H, m), 8.66-8.8 (3H, m),ylamino)ethyl)piperidine-1- 9.12 (0.7H, s), 9.18 (0.3H, s), carboxylate13.0-13.15 (1H, m) 153 2-(1-(1- 508 1.15-1.3 (8H, m), 1.52-1.6 (1H, m),(ethylsulfonyl)piperidin-4- 1.82-1.95 (2H, m), yl)ethylamino)-4-(5-2.7-2.85 (2H, m), 2.92-2.98 (2H, m), (trifluoromethyl)-1H- 3.58-3.65(2H, m), 4.03-4.1 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.28-8.31 (1H, m),8.7-8.8 (3H, m), yl)pyrimidine-5-carbonitrile 9.12-9.18 (1H, m),13.0-13.1 (1H, m) 154 2-((R)-1-(4-(1- 522 methylpiperidin-4-yloxy)phenyl)ethylamino)- 4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 155 2-(1-(4- 487(methylsulfonyl)phenyl)ethylamino)- 4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 156 benzyl4-(1-(5-cyano-4-(5- 550 1.21 (5H, m), 1.76 (3H, m),(trifluoromethyl)-1H- 2.77 (2H, m), 4.05 (3H, m), 5.03 (2H,pyrrolo[2,3-b]pyridin-3- m), 7.34 (5H, m), 8.27 (1H, m), yl)pyrimidin-2-8.66 (3H, m), 9.13 (1H, m), ylamino)ethyl)piperidine-1- 13.04 (1H)carboxylate 157 4-(1-(5-cyano-4-(5- 487 1.21 (5H, m), 1.63 (3H, m),(trifluoromethyl)-1H- 2.68 (2H, m), 2.70 (6H, m), 2.74 (2H,pyrrolo[2,3-b]pyridin-3- m), 4.03 (1H, m), 8.26 (1H, m), yl)pyrimidin-2-8.66 (3H, m), 9.11 (1H, m), ylamino)ethyl)-N,N- 13.08 (1H)dimethylpiperidine-1- carboxamide 158 2-(1-(1- 520 0.85-0.98 (4H, m),1.15-1.3 (5H, (cyclopropylsulfonyl)piperidin- m), 1.6-1.7 (1H, m),1.8-1.9 (2H, 4-yl)ethylamino)-4-(5- m), 2..7-2.85 (2H, m),(trifluoromethyl)-1H- 3.6-3.7 (2H, m), 4.05-4.15 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.3-8.37 (1H, m), 8.65-8.8 (3H, m),yl)pyrimidine-5-carbonitrile 9.1-9.2 (1H, m), 13.05-13.15 (1H, m) 1592-(1-(1- 484 0.65 (4H, m), 1.22 (6H, m),(cyclopropanecarbonyl)piperidin- 1.84 (4H, m), 3.02 (1H, m), 4.06 (1H,4-yl)ethylamino)-4-(5- m), 4.35 (2H, m), 8.27 (1H, m),(trifluoromethyl)-1H- 8.67 (3H, m), 9.14 (1H, m),pyrrolo[2,3-b]pyridin-3- 13.08 (1H, m) yl)pyrimidine-5-carbonitrile 1604-(1-(5-cyano-4-(5- 473 1.04 (2H, m), 1.22 (3H, m),(trifluoromethyl)-1H- 1.70 (3H, m), 2.50 (3H, m), 2.54 (2H,pyrrolo[2,3-b]pyridin-3- m), 3.99 (3H, m), 6.30 (1H, br s),yl)pyrimidin-2- 8.26 (1H, m), 8.67 (3H, m), ylamino)ethyl)-N- 9.14 (1H,m), 13.03 (1H, s) methylpiperidine-1- carboxamide 1612-((S)-1-(4-((S)-1- 508 1.55 (3H, m), 1.99 (1H, m), methylpyrrolidin-3-2.23 (1H, m), 2.84-2.90 (3H, m), yloxy)phenyl)ethylamino)- 3.67 (2H, m),5.10 (1H, m), 5.30 (1H, 4-(5-(trifluoromethyl)-1H- m), 6.88-6.96 (2H,m), pyrrolo[2,3-b]pyridin-3- 7.34-7.40 (2H, m), 8.70-8.75 (3H, m),yl)pyrimidine-5-carbonitrile 8.82 (1H, m), 9.00-9.21 (1H, m), 9.99 (1H,m), 13.09 (1H, m) mixture of rotamers 162 2-(1-(6-(4- 509 1.33-1.47 (2H,m), 1.54 (3H, d), hydroxypiperidin-1- 1.70-1.76 (2H, m), 2.95-3.05 (2H,yl)pyridin-3-yl)ethylamino)- m), 3.60-3.73 (1H, m),4-(5-(trifluoromethyl)-1H- 3.90-3.99 (2H, m), 4.62-4.66 (1H, m),pyrrolo[2,3-b]pyridin-3- 5.18-5.24 (1H, m), 6.80 (1H, dd),yl)pyrimidine-5-carbonitrile 7.54-7.59 (1H, m), 8.07 (0.5H, s), 8.14(0.5H, s), 8.69-8.74 (4H, m), 9.06 (0.5H, s), 9.19 (0.5H, s), 13.04 (1H,br s); ~1:1 mixture of rotamers 163 4-((1R)-1-(5-cyano-4-(5- 466 1.57(3H, m), 2.72-2.77 (3H, m), (trifluoromethyl)-1H- 5.34 (1H, m),7.44-7.50 (2H, m), pyrrolo[2,3-b]pyridin-3- 7.73-7.80 (2H, m), 8.31-8.36(1H, yl)pyrimidin-2- m), 8.67-8.73 (3H, m), 8.86 (1H, ylamino)ethyl)-N-m), 8.94-9.22 (1H, m), 13.02 (1H, methylbenzamide m) mixture of rotamers164 4-((1S)-1-(5-cyano-4-(5- 466 1.56 (3H, m), 2.72-2.77 (3H, m),(trifluoromethyl)-1H- 5.34 (1H, m), 7.44-7.50 (2H, m),pyrrolo[2,3-b]pyridin-3- 7.73-7.80 (2H, m), 8.31-8.36 (1H,yl)pyrimidin-2- m), 8.67-8.73 (3H, m), 8.85 (1H, ylamino)ethyl)-N- m),8.94-9.22 (1H, m), 13.00 (1H, methylbenzamide m) mixture of rotamers 1652-(1-(1-tosylpiperidin-4- 570 1.17 (5H, m), 1.46 (1H, m),yl)ethylamino)-4-(5- 1.83 (2H, m), 2.15 (2H, m), 2.34 (3H,(trifluoromethyl)-1H- s), 3.66 (2H, m), 3.96 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.40 (2H, m), 7.60 (2H, m),yl)pyrimidine-5-carbonitrile 8.19 (1H, m), 8.69 (3H, m), 9.06 (1H, m),13.08 (1H, s) 166 2-(1-(1- 455 1.2-1.4 (4H, m), 1.5-1.65 (1H, m),(cyanomethyl)piperidin-4- 1.85-1.98 (2H, m), 2.90-3.12 (1H,yl)ethylamino)-4-(5- m), 3.7-4.1 (3H, m), 8.23-8.3 (1H,(trifluoromethyl)-1H- m), 8.65-8.8 (3H, m), 9.1-9.2 (1H,pyrrolo[2,3-b]pyridin-3- m) yl)pyrimidine-5-carbonitrile 1672-(1-(6-(piperazin-1- 494 1.54 (3H, d), 2.72-2.76 (4H, m),yl)pyridin-3-yl)ethylamino)- 5.18-5.26 (1H, m), 6.76 (1H, dd),4-(5-(trifluoromethyl)-1H- 7.56-7.61 (1H, m), 8.08 (0.5H, s),pyrrolo[2,3-b]pyridin-3- 8.16 (0.5H, s), 8.68-8.72 (4H, m),yl)pyrimidine-5-carbonitrile 9.05 (0.5H, s), 9.18 (0.5H, s). Water peakobscures some signals, ~1:1 mixture of rotamers 168N-(4-((1R)-1-(5-cyano-4-(5- 528 0.72-0.9 (4H, m), 1.48 (3H, d),(trifluoromethyl)-1H- 3.12-3.14 (2H, m), 4.02-4.05 (1H,pyrrolo[2,3-b]pyridin-3- m), 5.25-5.32 (1H, m), yl)pyrimidin-2-7.05-7.16 (2H, m), 7.25-7.33 (2H, m),ylamino)ethyl)phenyl)cyclopropanesulfonamide 8.63-8.71 (3H, m), 8.75-8.8(1H, m), 8.92 (0.6H, s), 9.18 (0.4H, s), 9.5-9.6 (1H, m), 12.92-12.98(1H, m) 169 N-(4-((1R)-1-(5-cyano-4-(5- 516 1.1-1.25 (3H, m), 1.58 (3H,d), (trifluoromethyl)-1H- 2.95-3.07 (2H, m), 5.3-5.37 (1H,pyrrolo[2,3-b]pyridin-3- m), 7.12-7.22 (2H, m), yl)pyrimidin-2-7.32-7.42 (2H, m), 8.7-8.8 (3H, m),ylamino)ethyl)phenyl)ethanesulfonamide 8.8-8.82 (1H, m), 8.95 (0.6H, s),9.22 (0.4H, s), 9.71-9.76 (1H, m), 13.0-13.1 (1H, m) 1704-((1R)-1-(5-cyano-4-(5- 480 1.05-1.10 (3H, m), 1.56 (3H, m),(trifluoromethyl)-1H- 3.21 (2H, m), 5.30-5.37 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.43-7.49 (2H, m), 7.74-7.81 (2H,yl)pyrimidin-2- m), 8.34 (1H, m), 8.67-8.74 (3H, ylamino)ethyl)-N- m),8.88 (1H, m), 8.95-9.23 (1H, ethylbenzamide m), 13.04 (1H, br s) 1714-((1R)-1-(5-cyano-4-(5- 492 0.51-0.54 (2H, m), 0.64-0.69 (2H,(trifluoromethyl)-1H- m), 1.55 (3H, m), 2.78-2.82 (1H,pyrrolo[2,3-b]pyridin-3- m), 5.33 (1H, m), 7.42-7.49 (2H,yl)pyrimidin-2- m), 7.71-7.78 (2H, m), 8.29 (1H, ylamino)ethyl)-N- m),8.67-8.74 (3H, m), 8.88 (1H, cyclopropylbenzamide m), 8.96-9.22 (1H, m),13.06 (1H, br s) 172 4-((1R)-1-(5-cyano-4-(5- 494 1.10-1.15 (6H, m),1.56 (3H, m), (trifluoromethyl)-1H- 4.03-4.08 (1H, m), 5.31-5.37 (1H,pyrrolo[2,3-b]pyridin-3- m), 7.43-7.49 (2H, m), yl)pyrimidin-2-7.74-7.81 (2H, m), 8.08 (1H, m), ylamino)ethyl)-N- 8.67-8.74 (3H, m),8.89 (1H, m), isopropylbenzamide 8.97-9.23 (1H, m), 13.05 (1H, br s) 1732-(1-(1- 469 0.914 (3H, m), 1.34-1.40 (2H, (cyanomethyl)piperidin-4- m),1.50-1.98 (7H, m), 2.55 (1H, yl)propylamino)-4-(5- m), 3.13 (2H, m),3.79 (2H, m), (trifluoromethyl)-1H- 8.16 (1H, m), 8.71 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.14 (1H, m), 13.05 (1H, s)yl)pyrimidine-5-carbonitrile 174 2-(1-(1-acetylpiperidin-4- 472 1.04(3H, m), 1.05-1.16 (2H, m), yl)propylamino)-4-(5- 1.52 (1H, m), 1.74(5H, m), (trifluoromethyl)-1H- 1.96 (3H, m), 2.92 (1H, m), 3.99 (2H,pyrrolo[2,3-b]pyridin-3- m), 4.41 (1H, m), 8.19 (1H, m),yl)pyrimidine-5-carbonitrile 8.69 (3H, m), 9.11 (1H, m), 13.08 (1H, s)175 2-(1-(1- 522 0.91 (3H, m), 1.25 (5H, m), (ethylsulfonyl)piperidin-4-1.72 (1H, m), 1.74-1.80 (6H, m), yl)propylamino)-4-(5- 2.72 (2H, m),3.01 (2H, m), 4.01 (1H, (trifluoromethyl)-1H- m), 8.23 (1H, m), 8.73(3H, m), pyrrolo[2,3-b]pyridin-3- 9.12 (1H, m), 13.09 (1H, s)yl)pyrimidine-5-carbonitrile 176 4-((1R)-1-(5-cyano-4-(5- 452 1.56 (3H,m), 5.30-5.37 (1H, m), (trifluoromethyl)-1H- 7.28 (1H, m), 7.43-7.49(2H, m), pyrrolo[2,3-b]pyridin-3- 7.77-7.92 (3H, M), 8.68-8.73 (3H,yl)pyrimidin-2- m), 8.90-9.23 (2H, m), 13.06 (1H,ylamino)ethyl)benzamide m) 177 N-(4-((1R)-1-(5-cyano-4-(5- 520 1.54 (3H,m), 2.95-3.00 (3H, m), (trifluoromethyl)-1H- 5.25-5.34 (1H, m),7.11-7.34 (3H, pyrrolo[2,3-b]pyridin-3- m), 8.68-8.73 (3H, m), 8.82 (1H,yl)pyrimidin-2- m), 8.90-9.21 (1H, m), 9.53 (1H, ylamino)ethyl)-2- m),13.04 (1H, m) fluorophenyl)methanesulfonamide 178 2-(1-(1-(prop-2- 4541.22-1.26 (3H, m), 1.41-1.47 (2H, ynyl)piperidin-4- m), 1.78 (1H, m),2.02 (2H, m), yl)ethylamino)-4-(5- 2.97 (2H, m), 3.89 (2H, m),(trifluoromethyl)-1H- 4.04 (3H, m), 8.29-8.35 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.70-8.77 (3H, m), 9.10-9.17 (1H, m),yl)pyrimidine-5-carbonitrile 9.78 (1H, m), 13.06 (1H, m) 1792-((R)-1-((1r,4R)-4- 431 (CDCl₃) 1.18-1.36 (7H, m),hydroxycyclohexyl)ethylamino)- 1.90-2.07 (4H, m), 3.61 (1H, m),4-(5-(trifluoromethyl)- 4.12-4.22 (2H, m), 5.64-5.65 (1H, m),1H-pyrrolo[2,3-b]pyridin-3- 8.58.55 (1H, m), 8.74 (1H, s),yl)pyrimidine-5-carbonitrile 8.8.83 (1H, m), 9.18 (1H, m), 10.09 (1H, s)180 2-((R)-1-((1s,4S)-4- 431 hydroxycyclohexyl)ethylamino)-4-(5-(trifluoromethyl)- 1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 181 4-(1-(5-cyano-4-(5- 544 (CDCl₃) 1.05(6H, m), 1.75 (3H, (trifluoromethyl)-1H- m), 3.19 (4H, s), 5.46 (1H, s),pyrrolo[2,3-b]pyridin-3- 7.08 (1H, d), 7.53 (2H, d), 7.78 (2H,yl)pyrimidin-2- d), 8.55 (1H, s), 8.70 (1H, s), ylamino)ethyl)-N,N- 8.91(1H, s), 9.22 (1H, d), 11.27 (1H, diethylbenzenesulfonamide d) 1822-(1-(1- 536 0.91 (3H, m), 1.26 (8H, m), (isopropylsulfonyl)piperidin-1.55 (1H, m), 1.91 (5H, m), 2.75 (2H, 4-yl)propylamino)-4-(5- m), 3.54(2H, m), 4.01 (1H, m), (trifluoromethyl)-1H- 8.19 (1H, m), 8.73 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.12 (1H, m), 13.08 (1H, s)yl)pyrimidine-5-carbonitrile 183 2-(1-(1-(2- 488 1.22 (5H, m), 1.83 (3H,m), methoxyacetyl)piperidin-4- 2.93 (1H, m), 3.30 (3H, m), 3.95 (2H,yl)ethylamino)-4-(5- m), 4.01 (3H, m), 4.41 (1H, m),(trifluoromethyl)-1H- 8.28 (1H, m), 8.73 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.15 (1H, m), 13.08 (1H, s)yl)pyrimidine-5-carbonitrile 184 2-(1-(1-(3- 502 1.23 (5H, m), 1.81 (3H,m), methoxypropanoyl)piperidin- 3.10 (1H, m), 3.21 (3H, m), 3.51 (2H,4-yl)ethylamino)-4-(5- m), 4.05 (3H, m), 4.58 (3H, m),(trifluoromethyl)-1H- 8.28 (1H, m), 8.73 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.15 (1H, m), 13.08 (1H, s)yl)pyrimidine-5-carbonitrile 185 2-((R)-1-(4- 439 1.55 (3H, m), 4.41(2H, m), (hydroxymethyl)phenyl)ethylamino)- 5.28-3.34 (1H, m), 7.21-7.29(2H, m), 4-(5- 7.33-7.38 (2H, m), 8.67-8.74 (3H, (trifluoromethyl)-1H-m), 8.84 (1H, m), 9.01-9.23 (1H, pyrrolo[2,3-b]pyridin-3- m), 13.03 (1H,m) yl)pyrimidine-5-carbonitrile 186 4-((1R)-1-(5-cyano-4-(5- 453 1.57(3H, m), 5.34 (1H, m), (trifluoromethyl)-1H- 7.49-7.55 (2H, m),7.86-7.93 (2H, m), pyrrolo[2,3-b]pyridin-3- 8.68-8.74 (2H, m), 8.85-9.23(2H, yl)pyrimidin-2- m), 12.82 (1H, br s), 13.05 (1H,ylamino)ethyl)benzoic acid m) 187 2-(1-(1-propionylpiperidin- 472 1.03(4H, m), 1.25 (5H, m), 4-yl)ethylamino)-4-(5- 1.75 (3H, m), 2.26 (2H,m), 2.95 (1H, (trifluoromethyl)-1H- m), 3.90 (1H, m), 4.05 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.51 (1H, m), 4.58 (3H, m),yl)pyrimidine-5-carbonitrile 8.25 (1H, m), 8.73 (3H, m), 9.15 (1H, m),13.09 (1H, s) 188 2-(1-(1-(2- 473 1.24 (6H, m), 1.89 (3H, m),aminoacetyl)piperidin-4- 2.51 (1H, m), 2.63 (1H, m), 3.01 (1H,yl)ethylamino)-4-(5- m), 4.12 (2H, m), 4.24 (1H, m),(trifluoromethyl)-1H- 7.98 (2H, m), 8.30 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.73 (3H, m), 9.16 (1H, m), 13.06 (1H,yl)pyrimidine-5-carbonitrile s) 189 2-(1-(1-(2- 487 1.22 (5H, m), 1.87(3H, m), (methylamino)acetyl)piperidin- 2.51 (3H, m), 2.53 (1H, m), 3.11(1H, 4-yl)ethylamino)-4-(5- m), 4.05 (4H, m), 4.41 (1H, m),(trifluoromethyl)-1H- 8.31 (1H, m), 8.59 (2H, m),pyrrolo[2,3-b]pyridin-3- 8.74 (3H, m), 9.16 (1H, m), 13.10 (1H,yl)pyrimidine-5-carbonitrile s) 190 4-((1R)-1-(5-cyano-4-(5- 516 1.61(3H, m), 2.55 (6H, m (trifluoromethyl)-1H- masked), 5.48 (1H, m), 7.67(4H, pyrrolo[2,3-b]pyridin-3- m), 8.71 (3H, m), 8.80 (1H, m),yl)pyrimidin-2- 8.90 (1H, m), 13.08 (1H, s) ylamino)ethyl)-N,N-dimethylbenzenesulfonamide 191 2-(1-(6-(3-cyclopropyl-3- 523 0.39-0.44(2H, m), 0.57-0.61 (2H, fluoroazetidin-1-yl)pyridin- m), 1.36-1.39 (1H,m), 1.55 (3H, 3-yl)ethylamino)-4-(5- d), 3.83-3.95 (4H, m),(trifluoromethyl)-1H- 5.22-5.27 (1H, m), 6.46 (1H, dd), 7.64 (1H,pyrrolo[2,3-b]pyridin-3- dd), 8.06 (0.5H, s), 8.15 (0.5H, s),yl)pyrimidine-5-carbonitrile 8.71-8.77 (4H, m), 9.03 (0.5H, s), 9.18(0.5H, s), 13.03 (0.5H, s), 13.09 (0.5H, s); 1:1 mixture of rotamers 1922-(1-(1-(2- 474 1.23 (5H, m), 1.82 (3H, m), hydroxyacetyl)piperidin-4-2.59 (1H, m), 2.85 (1H, m), 3.72 (1H, yl)ethylamino)-4-(5- m), 4.02 (3H,m), 4.40 (1H, m), (trifluoromethyl)-1H- 8.31 (1H, m), 8.68 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.13 (1H, m), 13.08 (1H, s)yl)pyrimidine-5-carbonitrile 193 2-(1-(1-(2- 501 1.23 (5H, m), 1.87 (3H,m), (dimethylamino)acetyl)piperidin- 2.54 (1H, m), 2.77 (6H, m), 3.03(1H, 4-yl)ethylamino)-4-(5- m), 3.72 (1H, m), 4.02-4.45 (5H,(trifluoromethyl)-1H- m), 8.31 (1H, m), 8.68 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.16 (1H, m), 9.46 (1H, m),yl)pyrimidine-5-carbonitrile 13.08 (1H, s) 194 2-(1-(6-(3-cyclopropyl-3-521 0.29-0.41 (4H, m), 1.14-1.19 (1H, hydroxyazetidin-1- m), 1.53 (3H,d), 3.60-3.75 (4H, yl)pyridin-3-yl)ethylamino)- m), 5.19-5.25 (1H, m),5.47 (1H, 4-(5-(trifluoromethyl)-1H- d), 6.36 (1H, dd), 7.55-7.60 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.02 (0.5H, s), 8.11 (0.5H, s),yl)pyrimidine-5-carbonitrile 8.70-8.76 (4H, m), 9.06 (0.5H, s), 9.18(0.5H, s), 13.05 (0.5H, br s), 13.11 (0.5H, br s); ~1:1 mixture ofrotamers 195 2-(1-(6-(4-cyclopropyl-4- 549 1.55 (4H, d), 2.05-2.25 (7H,m), hydroxypiperidin-1- 3.45-3.55 (4H, m), 4.45-4.55 (1H,yl)pyridin-3-yl)ethylamino)- m). 5.15-5.30 (2H, m),4-(5-(trifluoromethyl)-1H- 6.80-6.85 (1H, m), 7.55-7.65 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.09-8.16 (1H, m), 8.69-8.72 (4H, m),yl)pyrimidine-5-carbonitrile 9.06-9.18 (1H, m) 1964-((1R)-1-(5-cyano-4-(5- 488 1.57 (3H, m), 5.28-5.39 (1H, m),(trifluoromethyl)-1H- 7.22 (2H, m), 7.54-7.61 (2H, m),pyrrolo[2,3-b]pyridin-3- 7.73-7.80 (2H, m), 8.67-8.74 (3H,yl)pyrimidin-2- m), 8.94-9.24 (2H, m), 13.06 (1H,ylamino)ethyl)benzenesulfonamide m) 197 2-(1-(6-(4-ethyl-4- 537 0.81(3H, q), 1.31-1.47 (6H, m), hydroxypiperidin-1- 1.54 (3H, d), 3.11-3.22(2H, m), yl)pyridin-3-yl)ethylamino)- 3.81-3.89 (2H, m), 4.10 (1H, d),4-(5-(trifluoromethyl)-1H- 5.19-5.26 (1H, m), 6.79 (1H, dd),pyrrolo[2,3-b]pyridin-3- 7.55 (1H, dd), 8.09 (1H, d),yl)pyrimidine-5-carbonitrile 8.67-8.73 (4H, m), 9.12 (1H, d), 13.05 (1H,br s) 198 2-(1-(6-(4-hydroxy-4- 551 0.78-0.83 (6H, m), 1.36-1.49 (6H,isopropylpiperidin-1- m), 1.53 (3H, d), 2.99-3.10 (2H,yl)pyridin-3-yl)ethylamino)- m), 3.97-4.03 (3H, m),4-(5-(trifluoromethyl)-1H- 5.17-5.26 (1H, m), 6.78 (1H, dd), 7.56 (1H,pyrrolo[2,3-b]pyridin-3- dd), 8.09 (1H, d), 8.49-8.65 (3H,yl)pyrimidine-5-carbonitrile m), 8.77 (1H, d), 9.07 (1H, d) 1992-(1-(6-(4-fluoropiperidin- 511 1.53 (3H, d), 1.58-1.69 (2H, m),1-yl)pyridin-3- 1.80-1.94 (2H, m), 3.32-3.42 (2H, yl)ethylamino)-4-(5-m), 3.64-3.75 (2H, m), (trifluoromethyl)-1H- 4.77-4.88 (1H, d),5.21-5.27 (1H, m), pyrrolo[2,3-b]pyridin-3- 6.86 (1H, dd), 7.60 (1H, d),8.12 (1H, yl)pyrimidine-5-carbonitrile d), 8.50-8.65 (3H, m), 8.77 (1H,d), 9.16 (1H, d) 200 4-((1R)-1-(5-cyano-4-(5- 502 1.59 (3H, d), 2.31(1.5H, d), (trifluoromethyl)-1H- 2.40 (1.5H, d), 5.32-5.42 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.36-7.41 (1H, m), 7.62 (2H, dd),yl)pyrimidin-2- 7.73 (2H, dd), 8.85 (0.5H, s), ylamino)ethyl)-N-8.94-8.97 (1H, m), 9.23 (0.5H, s), methylbenzenesulfonamide 13.08 (1H,brd); ~1:1 mix of rotamers 201 2-(1-(6-(3-hydroxyazetidin- 481 1.53 (3H,d), 3.55-3.61 (2H, m), 1-yl)pyridin-3- 4.04-4.12 (2H, m), 5.19-5.25 (1H,yl)ethylamino)-4-(5- m), 5.59 (1H, dd), 6.36 (1H, dd),(trifluoromethyl)-1H- 7.54-7.59 (1H, m), 8.02 (0.5H, s),pyrrolo[2,3-b]pyridin-3- 8.11 (0.5H, s), 8.70-8.77 (4H, m),yl)pyrimidine-5-carbonitrile 9.06 (0.5H, s), 9.18 (0.5H, s), 13.07 (2H,br s); ~1:1 mixture of rotamers 202 N-((1R,4r)-4-((1R)-1-(5- 5081.19-1.27 (7H, m), 1.85-1.97 (2H, cyano-4-(5- m), 2.06-2.10 (2H, m),2.91 (3H, (trifluoromethyl)-1H- s), 3.16-3.22 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.08-4.17 (2H, m), 5.47-5.55 (1H, m),yl)pyrimidin-2- 8.43-8.50 (1H, m), 8.65-8.80 (2H, m),ylamino)ethyl)cyclohexyl)methanesulfonamide 9.02-9.14 (1H, m), 10.07(1H, br d) 203 N-((1S,4s)-4-((1R)-1-(5- 508 1.39-1.86 (11H, m), 2.97 &cyano-4-(5- 3.00 (3H rotamer s), 3.70-3.74 (1H, (trifluoromethyl)-1H-m), 4.27-4.32 (1H, s), pyrrolo[2,3-b]pyridin-3- 4.46-4.58 (1H, m),5.49-5.64 (1H, m), yl)pyrimidin-2- 8.48-8.58 (1H, m), 8.71-8.88 (2H, m),ylamino)ethyl)cyclohexyl)methanesulfonamide 9.10-9.23 (1H, m),9.56-10.10 (1H, m) 204 2-((R)-1-(piperidin-4- 416 1.1-1.35 (5H, m),1.6-1.85 (4H, yl)ethylamino)-4-(5- m), 3.0-3.15 (1H, m), 4.0-4.1 (1H,(trifluoromethyl)-1H- m), 8.2-8.3 (1H, m), 8.7-8.9 (3H,pyrrolo[2,3-b]pyridin-3- m), 9.1-9.2 (1H, m)yl)pyrimidine-5-carbonitrile 205 2-((R)-1-(1-(2- 474 1.05-1.2 (5H, m),1.75-1.95 (5H, hydroxyacetyl)piperidin-4- m), 2.85-2.95 (1H, m),yl)ethylamino)-4-(5- 3.63-3.68 (2H, m), 3.97-4.03 (2H, m),(trifluoromethyl)-1H- 4.4-4.5 (1H, m), 8.23-8.28 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.7-8.8 (3H, m), 9.1-9.2 (1H, m),yl)pyrimidine-5-carbonitrile 13.1-13.2 (1H, m) 2062-((R)-1-(1-(2-hydroxy-2- 502 1.1-1.35 (10H, m), 1.8-1.9 (5H,methylpropanoyl)piperidin- m), 4.0-4.1 (1H, m), 8.3-8.33 (1H,4-yl)ethylamino)-4-(5- m), 8.7-8.8 (3H, m), 9.1-9.17 (1H,(trifluoromethyl)-1H- m), 13.1-13.16 (1H, m) pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 207 2-((R)-1-(1-((R)-2- 488 1.05-1.25 (5H,m), 1.75-1.95 (3H, hydroxypropanoyl)piperidin- m), 2.8-2.96 (1H, m),4-yl)ethylamino)-4-(5- 4.4-4.55 (1H, m), 8.3-8.37 (1H, m),(trifluoromethyl)-1H- 8.65-8.8 (3H, m), 9.1-9.2 (1H, m),pyrrolo[2,3-b]pyridin-3- 13.1-13.17 (1H, m) yl)pyrimidine-5-carbonitrile208 N-((1R,4r)-4-((1R)-1-(5- 472 (CDCl₃) 1.07-1.31 (4H, m), cyano-4-(5-1.34 (3H, d), 1.51-1.62 (2H, m), (trifluoromethyl)-1H- 1.88-1.92 (1H,m), 1.97 (3H, s), pyrrolo[2,3-b]pyridin-3- 2.06-2.12 (2H, m), 3.71-3.81(1H, m), yl)pyrimidin-2- 4.14-4.25 (1H, m), 5.26 (1H, d),ylamino)ethyl)cyclohexyl)acetamide 5.52-5.64 (1H, 2 × d), 8.51-8.59 (1H,2 × s), 8.73-8.88 (2H, m), 9.10-9.23 (1H, 2 × s), 9.96-10.00 (1H, 2 × s)209 N-((1S,4s)-4-((1R)-1-(5- 472 (CDCl₃) 1.27-2.16 (14H, m), cyano-4-(5-4.24-4.29 (2H, m), 5.54-5.79 (1H, (trifluoromethyl)-1H- m), 6.10-6.32(1H, m), 8.44 (1H, pyrrolo[2,3-b]pyridin-3- s), 8.60-8.81 (2H, m),yl)pyrimidin-2- 9.07-9.09 (1H, 2 × s), 9.23 (1H, s),ylamino)ethyl)cyclohexyl)acetamide 10.09-10.53 (1H, 2 × s) 2102-((R)-1-(1-(2- 473 0.8-0.9 (1H, m), 0.9-1.0 (5H, m),aminoacetyl)piperidin-4- 1.6-1.7 (4H, m), 2.4-2.5 (1H, m),yl)ethylamino)-4-(5- 2.7-2.8 (1H, m), 3.8-3.9 (1H, m),(trifluoromethyl)-1H- 4.15-4.22 (1H, m), 7.7-7.8 (3H,pyrrolo[2,3-b]pyridin-3- m), 8.1-8.14 (1H, m),yl)pyrimidine-5-carbonitrile 8.5-8.58 (3H, m), 8.85-8.95 (1H, m),13.1-13.17 (1H, m) 211 N-((1R,4r)-4-((1R)-1-(5- 488 (CDCl₃) 1.27-1.34(5H, m), cyano-4-(5- 1.35 (3H, d), 1.85-2.14 (4H, m),(trifluoromethyl)-1H- 2.37-2.41 (1H, m), 3.77-3.83 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.11 (1H, s), 4.18-4.29 (1H, m),yl)pyrimidin-2- 5.52-5.65 (1H, 2 × d), 6.21 (1H,ylamino)ethyl)cyclohexyl)- d), 8.51-8.87 (3H, m), 2-hydroxyacetamide9.10-9.23 (1H, 2 × s), 9.74-9.80 (1H, 2 × br s) 212N-((1S,4s)-4-((1R)-1-(5- 488 (CDCl₃) 1.04-1.74 (12H, m), cyano-4-(5-2.01-2.47 (1H, m), 3.94-4.22 (4H, (trifluoromethyl)-1H- m), 5.52-5.65(1H, 2 × d), pyrrolo[2,3-b]pyridin-3- 6.40 (1H, d), 8.41-8.86 (3H, m),yl)pyrimidin-2- 9.01-9.17 (1H, 2 × s), 9.62-9.71 (1H, 2 × brylamino)ethyl)cyclohexyl)- s) 2-hydroxyacetamide 213 2-((R)-1-(1- 5221.15-1.28 (11H, m), (isopropylsulfonyl)piperidin- 1.7-1.8 (1H, m),1.85-1.95 (2H, m), 4-yl)ethylamino)-4-(5- 2.75-2.9 (2H, m), 3.28-3.33(1H, m), (trifluoromethyl)-1H- 3.6-3.7 (2H, m), 4.02-4.1 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.3-8.36 (1H, m), 8.7-8.8 (3H, m),yl)pyrimidine-5-carbonitrile 9.1-9.17 (1H, m), 13.05-13.12 (1H, m) 2142-(1-(3- 399 Mixture of rotamers 1.10-1.25 (3H,methylenecyclobutyl)ethylamino)- m), 2.35-2.85 (5H, m),4-(5-(trifluoromethyl)-1H- 4.20-4.35 (1H, m), 4.65-4.80 (2H, m),pyrrolo[2,3-b]pyridin-3- 8-8.15 (1H, m), 8.55-8.7 (2H, m),yl)pyrimidine-5-carbonitrile 8.80 (0.3H, s), 8.90 (0.7H, s), 9.10 (1H,s), 12.80-13.40 (1H, br s), Mixture of rotamers 215 2-((R)-1-(1-(2- 4601.25-1.4 (3H, m), 1.5-1.7 (2H, m), hydroxyethyl)piperidin-4- 1.8-2.0(3H, m), 2.85-3.0 (2H, m), yl)ethylamino)-4-(5- 3.1-3.25 (2H, m),3.5-3.6 (2H, m), (trifluoromethyl)-1H- 3.75-3.85 (2H, m), 4.1-4.23 (1H,m), pyrrolo[2,3-b]pyridin-3- 5.255.35 (1H, m), 8.3-8.4 (1H, m),yl)pyrimidine-5-carbonitrile 8.7-8.83 (3H, m), 8.9-9.02 (1H, m), 9.1-9.2(1H, m), 13.1-13.15 (1H, m) 216 2-((R)-1-(1-(3- 488 1.0-1.22 (5H, m),1.7-1.87 (3H, m), hydroxypropanoyl)piperidin-4- 2.55-2.65 (2H, m),2.9-3.02 (1H, m), yl)ethylamino)-4-(5- 3.6-3.9 (6H, m), 4.4-4.5 (1H, m),(trifluoromethyl)-1H- 8.32-8.36 (1H, m), 8.75-8.82 (3H,pyrrolo[2,3-b]pyridin-3- m), 9.1-9.08 (1H, m),yl)pyrimidine-5-carbonitrile 13.1-13.15 (1H, m) 217 2-((R)-1-(1-((S)-2-502 0.75-0.82 (H, m), 0.8-0.9 (2H, m), hydroxybutanoyl)piperidin-4-1.0-1.25 (4H, m), 1.35-1.52 (1H, m), yl)ethylamino)-4-(5- 1.8-1.95 (3H,m), 2.9-3.1 (1H, m), (trifluoromethyl)-1H- 4.1-4.2 (1H, m), 4.2-4.3 (1H,m), pyrrolo[2,3-b]pyridin-3- 4.4-4.5 (1H, m), 8.34-8.37 (1H, m),yl)pyrimidine-5-carbonitrile 8.7-8.82 (2H, m), 9.12-9.2 1H, m),13.1-13.15 (1H, m) 218 2-(4-((1R)-1-(5-cyano-4-(5- 473 1.2-1.3 (3H, m),1.55-1.7 (2H, m), (trifluoromethyl)-1H- 1.75-1.95 (3H, m), 2.9-3.1 (2H,m), pyrrolo[2,3-b]pyridin-3- 3.5-3.57 (2H, m), 3.82-3.87 (2H, m),yl)pyrimidin-2- 4.1-4.2 (1H, m), 7.72 (1H, s),ylamino)ethyl)piperidin-1- 7.95 (1H, s), 8.32-8.42 (1H, m), yl)acetamide8.8-8.9 (3H, m), 9.1-9.2 (1H, m), 9.35-9.45 (1H, m), 13.1-13.15 (1H, m)219 2-((R)-1-(1-((R)-2- 502 0.8-0.9 (3H, m), 1.1-1.15 (2H, m),hydroxybutanoyl)piperidin-4- 1.2-1.26 (3H, m), 1.32-1.53 (2H, m),yl)ethylamino)-4-(5- 1.78-1.9 (3H, m), 2.88-3.0 (1H, m),(trifluoromethyl)-1H- 3.95-4.1 (2H, m), 4.1-4.2 (2H, m),pyrrolo[2,3-b]pyridin-3- 4.4-4.5 (1H, m), 8.3-8.34 (1H, m),yl)pyrimidine-5-carbonitrile 8.7-8.8 (3H, m), 9.1-9.2 (1H, m),13.1-13.15 (1H, m) 220 2-((R)-1-(1-(1- 500 0.72-0.78 (2H, m), 0.85-0.92(2H, hydroxycyclopropanecarbonyl)piperidin- m), 1.1-1.27 (4H, m),1.75-1.9 (4H, 4-yl)ethylamino)-4- m),, 4.0-4.1 (2H, m), 4.3-4.5 (2H,(5-(trifluoromethyl)-1H- m), 8.3-8.34 (1H, m), 8.7-8.82 (3H,pyrrolo[2,3-b]pyridin-3- m), 9.1-9.2 (1H, m), 13.1-13.15 (1H,yl)pyrimidine-5-carbonitrile m) 221 2-(1-(1-(2-hydroxy-2- 474 1.06-1.24(9H, m), 2.76-2.81 (1H, methylpropanoyl)azetidin-3- m), 3.60 maskedsignal, yl)ethylamino)-4-(5- 3.84-3.96 (1H, m), 4.07-4.16 (1H, m),(trifluoromethyl)-1H- 4.34-4.51 (2H, m), 8.31-8.39 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.69-8.75 (3H, m), 9.13 (1H,yl)pyrimidine-5-carbonitrile m)13.06-13.13 (1H, m) 222 2-(1-(1-((R)-2-460 0.34-0.40 (1H, m), 0.47-0.56 (5H, hydroxypropanoyl)azetidin-3- m),2.15 (1H, m), 3.01-3.10 (1H, m), yl)ethylamino)-4-(5- 3.30-3.47 (3H, m),3.62-3.78 (2H, (trifluoromethyl)-1H- m), 4.10 masked signal,pyrrolo[2,3-b]pyridin-3- 7.76-7.87 (2H, m), 8.00-8.05 (1H, m),yl)pyrimidine-5-carbonitrile 8.49-8.53 (1H, m) 2232-((R)-1-(6-(2-(pyrrolidin-1- 522 1.56 (3H, d), 1.89-1.93 (4H, m),yl)ethylamino)pyridin-3- 2.50 (2H, masked by DMSO), 3.33 (4H,yl)ethylamino)-4-(5- masked by water), 3.54-3.60 (2H, m),(trifluoromethyl)-1H- 5.10-5.30 (1H, m), 6.55-6.85 (1H, brpyrrolo[2,3-b]pyridin-3- s), 7.55-7.80 (1H, br s). 7.95 (0.5 H,yl)pyrimidine-5-carbonitrile s), 8.04 (0.5H, s), 8.65-8.80 (4H, m), 9.01(0.5H, s), 9.18 (0.5H, s), 9.50-9.70 (1H, br s), 13.15 (1H, d) 2242-((R)-1-(1-(3- 487 1.04-1.24 (6H, m), 1.79 (3H, m),aminopropanoyl)piperidin-4- 2.59-2.67 (1H, m), 2.94-2.99 (3H,yl)ethylamino)-4-(5- m), 3.82 (1H, m), 4.04 (1H, m),(trifluoromethyl)-1H- 4.45 (1H, m), 7.58 (3H, br s), 8.32 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.68-8.76 (3H, m), 9.10 (1H, m),yl)pyrimidine-5-carbonitrile 13.06-13.12 (1H, m) mixture of rotamers 2252-((R)-1-(1-((R)-2- 487 1.04-1.31 (8H, m), 1.79-1.91 (3H,aminopropanoyl)piperidin-4- m), 2.64 (1H, m), 3.03 (1H, m),yl)ethylamino)-4-(5- 3.84-4.05 (2H, m), 4.35-4.45 (1H, m),(trifluoromethyl)-1H- 7.99-8.01 (3H, m), 8.35 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.68-8.76 (3H, m), 9.10-9.17 (1H,yl)pyrimidine-5-carbonitrile m), 13.06-13.12 (1H, m) 2262-((R)-1-(1-((R)-2- 501 0.85-0.90 (3H, m), 0.92-1.24 (5H,aminobutanoyl)piperidin-4- m), 1.63-1.91 (5H, m), 2.62 (1H, m),yl)ethylamino)-4-(5- 2.99-3.10 (1H, m), 3.88-4.07 (1H,(trifluoromethyl)-1H- m), 4.32 (1H, m), 4.43 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.02-8.05 (3H, m), 8.34 (1H, m),yl)pyrimidine-5-carbonitrile 8..67-8.75 (3H, m), 9.09-9.17 (1H, m),13.14 (1H, m) mixture of rotamers 227 2-((R)-1-(1-(azetidine-3- 4991.03-1.28 (5H, m), 1.79 (3H, m), carbonyl)piperidin-4- 2.62 (1H, m),2.91 (1H, m), yl)ethylamino)-4-(5- 3.51 (1H, m), 3.82 masked signal,(trifluoromethyl)-1H- 4.42 (1H, m), 8.29-8.33 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.67-8.74 (4H, m), 8.87 (1H, br s),yl)pyrimidine-5-carbonitrile 9.09-9.16 (1H, m), 13.07-13.14 (1H, m) 2282-((R)-1-(1-((S)-2- 488 / hydroxypropanoyl)piperidin-4-yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 229 2-((R)-1-(1-((R)-2-amino-3- 5150.84-1.24 (11H, m), 1.82-1.99 (4H, methylbutanoyl)piperidin-4- m), 2.64(1H, m), 3.02 (1H, m), 4.03 yl)ethylamino)-4-(5- masked signal, 4.25(1H, br s), (trifluoromethyl)-1H- 4.56 (1H, m), 7.98-8.01 (3H, m),pyrrolo[2,3-b]pyridin-3- 8.33 (1H, m), 8.67-8.75 (3H, m),yl)pyrimidine-5-carbonitrile 9.09-9.17 (1H, m), 13.09-13.15 (1H, m)rotamers observed 230 2-((R)-1-(1-((S)-3,3,3- 542 / trifluoro-2-hydroxypropanoyl)piperidin-4- yl)ethylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 2312-((R)-1-(1-(2- 486 1.0-1.22 (5H, m), 1.8-1.95 (3H, m),oxopropanoyl)piperidin-4- 2.3-2.4 (3H, m), 2.65-2.8 (1H, m),yl)ethylamino)-4-(5- 3.0-3.14 (1H, m), 3.6-3.72 (1H, m),(trifluoromethyl)-1H- 4.08-4.12 (1H, m), 4.3-4.4 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.2-8.6 (1H, m), 8.7-8.82 (3H, m),yl)pyrimidine-5-carbonitrile 9.1-9.2 (1H, m), 13.1-13.17 (1H, m) 2322-(1-(azetidin-3- 388 1.41 (3H, d), 2.43 (1H, m), 3.02 (2H,yl)ethylamino)-4-(5- m), 3.91 (1H, m), 4.28 (1H, m),(trifluoromethyl)-1H- 4.42 (1H, m), 8.10 (3H, br s),pyrrolo[2,3-b]pyridin-3- 8.84-9.22 (4H, m), 10.82 (1H, br s)yl)pyrimidine-5-carbonitrile 233 2-((R)-1-(1-(2- 483 1.0-1.25 (5H, m),1.75-1.9 (3H, m), cyanoacetyl)piperidin-4- 2.5-2.7 (1H, m), 2.95-3.1(1H, m), yl)ethylamino)-4-(5- 3.65-3.8 (1H, m), 3.95-4.1 (3H, m),(trifluoromethyl)-1H- 4.38-4.46 (1H, m), 8.3-8.37 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.7-8.82 (3H, m), 9.1-9.2 (1H, m),yl)pyrimidine-5-carbonitrile 13.1-13.15 (1H, m) 2342-(1-(1-(2-aminoacetyl)-4- 491 1.3-1.38 (3H, m), 1.65-2.0 (4H, m),fluoropiperidin-4- 2.8-2.9 (1H, m), 3.3-3.4 (1H, m),yl)ethylamino)-4-(5- 3.68-3.78 (1H, m), 3.8-4.0 (2H, m),(trifluoromethyl)-1H- 4.33-4.43 (1H, m), 4.43-4.53 (1H,pyrrolo[2,3-b]pyridin-3- m), 7.95-8.07 (2H, m),yl)pyrimidine-5-carbonitrile 8.45-8.58 (1H, m), 8.72-8.77 (3H, m),9.1-9.13 (0.5H, m), 9.26-9.28 (0.5H, m), 13.1-13.15 (1H, m) 2352-(1-(1-(2- 445 / aminoacetyl)azetidin-3- yl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 236 2-((R)-1-(1-((S)-pyrrolidine-2- 5131.06-1.25 (5H, m), 1.68-1.92 (6H, carbonyl)piperidin-4- m), 2.33 (1H,m), 2.65 (1H, m), yl)ethylamino)-4-(5- 3.00-3.23 (3H, m), 3.86 (1H, m),(trifluoromethyl)-1H- 4.06 (1H, m), 4.40 (1H, m), 4.54 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.33 (1H, m), 8.45 (1H, m),yl)pyrimidine-5-carbonitrile 8.68-8.76 (3H, m), 9.09-9.27 (2H, m),13.06-13.13 (1H, m) 237 2-(1-(4-fluoro-1-((R)-2- 506 1.1-1.2 (3H, m),1.27-1.33 (3H, m), hydroxypropanoyl)piperidin-4- 1.6-2.0 (5H, m),2.75-2.85 (1H, m), yl)ethylamino)-4-(5- 3.2-3.3 (1H, m), 4.0-4.1 (1H,m), (trifluoromethyl)-1H- 4.3-4.6 (3H, m), 8.4-8.55 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.73-8.82 (3H, m), 9.1-9.15 (0.6H, m),yl)pyrimidine-5-carbonitrile 9.26-9.28 (0.4H, m), 13.1-13.15 (1H, m) 2382-(1-(1-(cyanomethyl)-4- 473 1.25-1.3 (3H, m), 1.7-2.0 (5H, m),fluoropiperidin-4- 2.72-2.82 (1H, m), 4.5-4.6 (1H, m),yl)ethylamino)-4-(5- 8.45 (0.6H, d), 8.55 (0.4H, d),(trifluoromethyl)-1H- 8.74-8.82 (3H, m), 9.12 (0.6H, s),pyrrolo[2,3-b]pyridin-3- 9.27 (0.4H, s), 13.1-1.3.18 (1H, m)yl)pyrimidine-5-carbonitrile 239 2-((R)-1-(1-((S)-2-amino-3- 5031.04-1.25 (5H, m), 1.85 (3H, m), hydroxypropanoyl)piperidin-4- 2.56-2.67(1H, m), 3.04 (1H, m), yl)ethylamino)-4-(5- 3.17 (2H, s), 3.68 (2H, m),3.89 (1H, (trifluoromethyl)-1H- m), 4.06 (1H, m), 4.28-4.45 (2H, m),pyrrolo[2,3-b]pyridin-3- 8.04 (3H, br s), 8.32 (1H, m),yl)pyrimidine-5-carbonitrile 8.68-8.75 (3H, m), 9.10 (1H, m),13.06-13.13 (1H, m) 240 2-((R)-1-(1-((R)-2-amino-3- 503 /hydroxypropanoyl)piperidin-4- yl)ethylamino)-4-(5- (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 2412-((R)-1-(1-((R)-2-amino-4- 529 0.87-0.93 (6H, m), 1.04-1.24 (5H,methylpentanoyl)piperidin-4- m), 1.39-1.93 (6H, m), 2.62 (1H, m),yl)ethylamino)-4-(5- 3.74 (2H, m), 4.35-4.47 (2H, m),(trifluoromethyl)-1H- 8.04-8.36 (4H, m), 8.67-8.75 (3H,pyrrolo[2,3-b]pyridin-3- m), 9.10-9.17 (1H, m),yl)pyrimidine-5-carbonitrile 13.08-13.14 (1H, m) 2422-((R)-1-(1-((2S,3R)-2-amino- 517 0.97-1.26 (8H, m), 1.82-1.88 (3H,3-hydroxybutanoyl)piperidin- m), 2.57-2.63 (1H, m),4-yl)ethylamino)-4-(5- 2.95-3.04 (1H, m), 4.12 masked signal,(trifluoromethyl)-1H- 4.28 (1H, m), 4.45 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.93-7.98 (3H, m), 8.33 (1H, m),yl)pyrimidine-5-carbonitrile 8.68-8.75 (3H, m), 9.10-9.16 (1H, m),13.07-13.13 (1H, m) 243 2-((R)-1-(1-((S)-2- 487 1.03-1.29 (8H, m), 1.84(3H, m), aminopropanoyl)piperidin-4- 2.65 (1H, m), 2.94-3.16 (1H, m),yl)ethylamino)-4-(5- 3.83 (1H, m), 4.06 (1H, m), (trifluoromethyl)-1H-4.28-4.44 (2H, m), 8.01 (3H, br s), pyrrolo[2,3-b]pyridin-3- 8.30-8.34(1H, m), 8.68-8.75 (3H, m), yl)pyrimidine-5-carbonitrile 9.09-9.16 (1H,m), 13.06-13.13 (1H, m) 244 2-((R)-1-(1-((S)-3- 501 1.03-1.24 (8H, m),1.78 (3H, m), aminobutanoyl)piperidin-4- 2.66 (1H, m), 2.97 (1H, m),yl)ethylamino)-4-(5- 3.84 (1H, m), 4.05 (1H, m), 4.45 (1H, m),(trifluoromethyl)-1H- 7.68 (3H, br s), 8.31-8.34 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.67-8.74 (3H, m), 9.09-9.17 (1H,yl)pyrimidine-5-carbonitrile m), 13.06-13.13 (1H, m) 2452-((R)-1-((1s,4S)-4-(4- 513 (CDCl₃) 1.06-1.13 (2H, m),methylpiperazin-1- 1.24-1.32 (2H, m), 1.28 (3H, d), 1.46 (3H,yl)cyclohexyl)ethylamino)-4- s), 1.54-1.98 (7H, m), 2.28-2.34 (3H,(5-(trifluoromethyl)-1H- m), 2.38-2.70 (4H, m), 3.70 (1H, 2 spyrrolo[2,3-b]pyridin-3- br s), 4.34-4.37 (1H, m),yl)pyrimidine-5-carbonitrile 5.63-5.69 (1H, m), 8.50-8.83 (3H, m), 9.23(1H, 2 × s) 246 2-((R)-1-(1-((1R,2S)-2- 527 1.10-1.24 (5H, m), 1.65-1.99(9H, aminocyclopentanecarbonyl)piperidin- m), 2.95-3.06 (1H, m),4-yl)ethylamino)-4-(5- 3.16-3.24 (1H, m), 3.98-4.05 (2H, m),(trifluoromethyl)-1H- 4.45 (1H, m), 7.78 (3H, br s),pyrrolo[2,3-b]pyridin-3- 8.31-8.35 (1H, m), 8.68-8.75 (3H, m),yl)pyrimidine-5-carbonitrile 9.10-9.16 (1H, m), 13.06-13.13 (1H, m)rotamers observed 247 2-((R)-1-(1-((S)-3-amino-4- 529 0.84-0.93 (6H, m),1.03-1.26 (5H, methylpentanoyl)piperidin-4- m), 1.77-1.86 (4H, m), 2.37(1H, m), yl)ethylamino)-4-(5- 2.57-2.73 (1H, m), 2.89-3.02 (1H,(trifluoromethyl)-1H- m), 3.26 (1H, m), 3.90- (1H, m),pyrrolo[2,3-b]pyridin-3- 4.06 (1H, m), 4.44-4.52 (1H, m),yl)pyrimidine-5-carbonitrile 7.64 (3H, br s), 8.32-8.35 (1H, m),8.68-8.75 (3H, m), 9.09-9.16 (1H, m), 13.06-13.13 (1H, m) rotamersobserved 248 2-((R)-1-(1-((R)-2-amino-2- 549 0.90-1.26 (5H, m),1.70-1.90 (2H, phenylacetyl)piperidin-4- m), 2.62 (1H, m), 2.99 (1H, m),yl)ethylamino)-4-(5- 3.75-4.05 (2H, m), 4.47 (1H, m),(trifluoromethyl)-1H- 5.53 (1H, m), 7.35-7.46 (5H, m),pyrrolo[2,3-b]pyridin-3- 8.14-8.34 (1H, m), 8.49 (3H, m),yl)pyrimidine-5-carbonitrile 8.66-8.78 (3H, m), 8.95-9.18 (1H, m),13.06-13.13 (1H, m) rotamers observed 249 2-((R)-1-(1-((2R,3S)-2-amino-517 1.06-1.25 (8H, m), 1.82-1.86 (3H, 3-hydroxybutanoyl)piperidin- m),2.58-2.67)1H, m), 4-yl)ethylamino)-4-(5- 2.96-3.02 (1H, m), 3.86 (1H,m), (trifluoromethyl)-1H- 3.97-4.05 (2H, m), 4.22 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.42-4.48 (1H, m), 7.92-7.98 (3H, m),yl)pyrimidine-5-carbonitrile 8.33-8.36 (1H, m), 8.68-8.75 (3H, m),9.10-9.17 (1H, m), 13.06-13.13 (1H, m) 250 (3R)-3-amino-4-(4-((1R)-1-(5-530 1.03-1.09 (1H, m), 1.21-1.25 (4H, cyano-4-(5-(trifluoromethyl)- m),2.43 masked signal, 1H-pyrrolo[2,3-b]pyridin-3- 2.59-2.67 (1H, m),2.96-3.08 (1H, m), yl)pyrimidin-2- 3.80-4.04 (3H, m), 4.41-4.55 (2H, m),ylamino)ethyl)piperidin-1-yl)- 7.26 (1H, m), 7.64 (1H, m),4-oxobutanamide 8.02-8.07 (3H, m), 8.31-8.35 (1H, m), 8.69-8.76 (3H, m),9.07-9.17 (1H, m), 13.05-13.12 (1H, m) rotamers observed 2512-((R)-1-(1-((R)-2-amino-3- 512 1.04-1.32 (5H, m), 1.86 (3H, m),cyanopropanoyl)piperidin-4- 2.60-2.67 (1H, m), 2.92-3.17 (3H,yl)ethylamino)-4-(5- m), 3.93-4.04 (2H, m), 4.43 (1H, m),(trifluoromethyl)-1H- 4.75 (1H, m), 8.32-8.43 (4H, m),pyrrolo[2,3-b]pyridin-3- 8.68-8.76 (3H, m), 9.09-9.17 (1H,yl)pyrimidine-5-carbonitrile m), 13.06-13.12 (1H, m) rotamers observed252 2-((R)-1-(1-((R)-2,5- 530 1.04-1.26 (5H, m), 1.50-1.92 (7H,diaminopentanoyl)piperidin-4- m), 2.58-2.77 (3H, m),yl)ethylamino)-4-(5- 2.99-3.07 (1H, m), 3.88-3.91 (1H, m),(trifluoromethyl)-1H- 4.04-4.06 (1H, m), 4.44 (2H, m),pyrrolo[2,3-b]pyridin-3- 7.74 (3H, m), 8.10-8.13 (3H, m),yl)pyrimidine-5-carbonitrile 8.35 (1H, t), 8.70-8.76 (3H, m), 9.10-9.17(1H, m), 13.08-13.14 (1H, m) 253 2-((R)-1-(1-((1s,3S)-3- 513 0.98-1.05(2H, m), 1.19-1.23 (3H, aminocyclobutanecarbonyl)piperidin- m),1.77-1.86 (3H, m), 4-yl)ethylamino)-4-(5- 2.17-2.24 (2H, m), 2.33-2.46(2H, m), (trifluoromethyl)-1H- 2.85-2.98 (1H, m), 3.05-3.16 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.02 (1H, m), 4.40 (1H, m),yl)pyrimidine-5-carbonitrile 7.90 (3H, m), 8.31 (1H, m), 8.68-8.75 (3H,m), 9.10-9.16 (1H, m), 1306-13.12 (1H, m) 254 2-((R)-1-(1-((S)-2,5- 5301.06-1.27 (5H, m), 1.40-1.66 (4H, diaminopentanoyl)piperidin-4- m),1.83-1.90 (3H, m), yl)ethylamino)-4-(5- 2.67-2.77 (2H, m), 2.99-3.08(1H, m), (trifluoromethyl)-1H- 3.87-4.12 (2H, m), 4.37-4.47 (2H, m),pyrrolo[2,3-b]pyridin-3- 7.68-7.73 (3H, m), 8.11 (3H, m),yl)pyrimidine-5-carbonitrile 8.34 (1H, m), 8.69-8.76 (3H, m), 9.09-9.16(1H, m), 13.07-13.14 (1H, m), rotamers observed 2552-((R)-1-(1-((S)-2-amino-3- 512 1.10-1.26 (5H, m), 1.81-1.88 (3H,cyanopropanoyl)piperidin-4- m), 2.62-2.67 (1H, m), yl)ethylamino)-4-(5-2.92-3.10 (3H, m), 3.96-4.10 (2H, m), (trifluoromethyl)-1H- 4.43 (1H,m), 4.71-4.81 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.30-8.43 (4H, m),8.69-8.76 (3H, m), yl)pyrimidine-5-carbonitrile 9.10-9.17 (1H, m),13.06-13.12 (1H, m) rotamers observed 256 2-((R)-1-(1-((R)-2-hydroxy-3-516 0.70-0.87 (6H, m), 0.85-1.23 (6H, methylbutanoyl)piperidin-4- m),1.76-1.81 (4H, m), 2.94 (1H, m), yl)ethylamino)-4-(5- 4.02 (3H, m), 4.40(1H, m), (trifluoromethyl)-1H- 8.31-8.33 (1H, m), 8.67-8.75 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.10-9.16 (1H, m), 13.04-13.10 (1H,yl)pyrimidine-5-carbonitrile m) rotamers observed 257 2-((1R)-1-(1-(2,3-504 1.05-1.24 (5H, m), 1.78-1.80 (3H, dihydroxypropanoyl)piperidin- m),2.93 (1H, m), 4.05 (2H, m), 4-yl)ethylamino)-4-(5- 4.29 (1H, m), 4.43(1H, m), 8.31 (1H, m), (trifluoromethyl)-1H- 8.67-8.75 (3H, m),9.10-9.17 (1H, pyrrolo[2,3-b]pyridin-3- m), 13.04-13.10 (1H, m)yl)pyrimidine-5-carbonitrile 258 2-(4-((1R)-1-(5-cyano-4-(5- 4871.11-1.24 (5H, m), 1.82 (3H, m), (trifluoromethyl)-1H- 2.62 (1H, m),3.03 (1H, m), pyrrolo[2,3-b]pyridin-3- 3.75-3.78 (1H, m), 4.05 (1H, m),yl)pyrimidin-2- 4.31 (1H, m), 7.60 (1H, m), 8.00 (1H, m),ylamino)ethyl)piperidin-1-yl)- 8.32 (1H, m), 8.67-8.76 (3H, m),2-oxoacetamide 9.10-9.17 (1H, m), 13.03-13.10 (1H, m) rotamers observed259 2-((R)-1-(1-((R)-azetidine-2- 499 1.06-1.24 (5H, m), 1.78-1.87 (3H,carbonyl)piperidin-4- m), 2.36 (1H, m), 2.61-2.82 (2H, m),yl)ethylamino)-4-(5- 2.91 (1H, m), 3.41 (1H, m), (trifluoromethyl)-1H-3.70 (1H, m), 4.38 (1H, m), 5.27 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.32(1H, m), 8.68-8.75 (4H, m), yl)pyrimidine-5-carbonitrile 9.10-9.16 (1H,m), 9.23 (1H, br s), 13.07-13.13 (1H, m) 260 2-((1R)-1-(1-(3-amino-2-503 1.08-1.24 (5H, m), 1.83 (3H, m), hydroxypropanoyl)piperidin-4- 2.60(1H, m), 2.87-3.09 (3H, m), yl)ethylamino)-4-(5- 4.47 (2H, m), 7.75 (3H,br s), (trifluoromethyl)-1H- 8.32 (1H, m), 8.67-8.75 (3H, m),pyrrolo[2,3-b]pyridin-3- 9.10-9.17 (1H, m), 13.07-13.13 (1H, m)yl)pyrimidine-5-carbonitrile rotamers observed 2612-((R)-1-((1r,4R)-4-(4- 513 (CDCl₃) 1.20-1.34 (6H, m),methylpiperazin-1- 1.38-2.23 (10H, m), 2.84 (3H, s),yl)cyclohexyl)ethylamino)-4- 3.00-3.09 (1H, m), 3.45-3.75 (6H, m),(5-(trifluoromethyl)-1H- 4.18-4.21 (1H, m), 5.47-5.92 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.48-8.87 (3H, m),yl)pyrimidine-5-carbonitrile 9.08-9.16 (1H, m), 9.92-10.03 (1H, m) 2622-((R)-1-(1-((2R,4R)-4- 529 1.10-1.25 (5H, m), 1.67-1.91 (4H,hydroxypyrrolidine-2- m), 2.60-2.73 (1H, m), carbonyl)piperidin-4-2.97-3.16 (3H, m), 3.72 (1H, m), 4.06 (1H, m), yl)ethylamino)-4-(5-4.36-4.51 (3H, m), 5.29 (1H, m), (trifluoromethyl)-1H- 8.34 (1H, m),8.50 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.69-8.76 (3H, m), 9.11-9.17 (1H,m), yl)pyrimidine-5-carbonitrile 9.34 (1H, m), 13.06-13.12 (1H, m) 2632-((R)-1-(1-((2R,4S)-4- 529 1.05-1.25 (5H, m), 1.83-1.94 (4H,hydroxypyrrolidine-2- m), 2.27 (1H, m), 2.65 (1H, m),carbonyl)piperidin-4- 2.97-3.13 (2H, m), 3.26 (2H, m),yl)ethylamino)-4-(5- 3.80 (1H, m), 4.06 (1H, m), 4.40 (2H, m),(trifluoromethyl)-1H- 4.67 (1H, m), 8.34 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.60 (1H, m), 8.69-8.76 (3H, m),yl)pyrimidine-5-carbonitrile 9.11-9.17 (1H, m), 9.54 (1H, m),13.06-13.12 (1H, m) rotamers observed 264 2-amino-N-((1R,4r)-4-((1R)-1-487 (CDCl₃) 1.12-1.35 (10H, m), (5-cyano-4-(5- 1.86-2.10 (4H, m), 3.34(2H, s), (trifluoromethyl)-1H- 3.35-3.42 (1H, m), 4.18-4.25 (1H, m),pyrrolo[2,3-b]pyridin-3- 5.52-5.60 (1H, 2 × d), 7.11-7.13 (1H, m),yl)pyrimidin-2- 8.51-8.59 (1H, 2 × s), 8.72-8.86 (2H,ylamino)ethyl)cyclohexyl)acetamide m), 9.10-9.23 (1H, 2 × s), 9.73 (1H,br s) 265 (2R)—N-((1R,4R)-4-((1R)-1-(5- 502 (CDCl₃) 1.20-1.35 (8H, m),1.44 (3H, cyano-4-(5-(trifluoromethyl)- d), 1.90-2.09 (4H, m), 2.34 (1H,d), 1H-pyrrolo[2,3-b]pyridin-3- 3.69-3.81 (1H, m), 4.18-4.28 (2H,yl)pyrimidin-2- m), 5.52 (0.33H, d), 5.58 (0.67H, d),ylamino)ethyl)cyclohexyl)-2- 6.27 (1H, d), 8.50 (0.66H, s),hydroxypropanamide 8.58 (0.33H, s), 8.72 (1H, s), 8.77 (0.33H, d), 8.86(0.67H, d), 9.09 (0.33H, s), 9.23 (0.67H, s), 9.64 (1H, br s) 2662-(1-(6-(4-hydroxy-1- 523 1.40-1.49 (2H, m), 1.59 (3H, d),methylpiperidin-4-yl)pyridin- 2.05-2.21 (2H, m), 2.16 (1.5H, s),3-yl)ethylamino)-4-(5- 2.16 (1.5H, s), 2.25-2.33 (2H, m),(trifluoromethyl)-1H- 2.50-2.55 (2H, m), 4.96 (1H, d),pyrrolo[2,3-b]pyridin-3- 5.31-5.41 (1H, m), 7.58-7.65 (1H,yl)pyrimidine-5-carbonitrile m), 7.78-7.87 (1H, m), 8.51 (0.5H, s), 8.57(0.5H, s), 8.70-8.72 (3H, m), 8.52-8.56 (1H, m), 8.97 (0.5H, s), 9.20(0.5H, s), 13.03 (1H, br s) 267 2-((R)-1-(6-(piperazin-1- 494 1.58 (3H,d), 2.3 (3H, s), yl)pyridin-3-yl)ethylamino)-4- 3.1-3.22 (4H, m),3.63-3.73 (4H, m), (5-(trifluoromethyl)-1H- 5.2-5.3 (1H, m), 6.87-6.96(1H, m), pyrrolo[2,3-b]pyridin-3- 7.65-7.75 (1H, m), 8.15 (0.6H, s),yl)pyrimidine-5-carbonitrile 8.26 (0.4H, s), 8.7-8.83 (5H, m), 9.03(0.6H, s), 9.22 (0.4H, s) 268 2-((R)-1-(2-((S)-1- 509 1.52-1.6 (3H, m),1.85-2.0 (2H, m), methylpyrrolidin-3- 2.82-2.93 (2H, m), 3.08-3.3 (1.5H,ylamino)pyrimidin-5- m), 3.52-3.8 (1.5H, m), yl)ethylamino)-4-(5-3.85-3.95 (1H, m), 4.45-4.55 (1H, m), (trifluoromethyl)-1H- 5.2-5.33(1H, m), 7.51-7.53 (0.55H, m), pyrrolo[2,3-b]pyridin-3- 7.67-7.70(0.45H, m), 8.4-8.52 (2H, m), yl)pyrimidine-5-carbonitrile 8.7-8.8 (4H,m), 9.05 90.55H, s), 9.18 (0.45H, s), 9.67-9.8 (1H, m) 2692-((S)-1-((1r,3S)-3- 403 1.1-1.5 (4H, m), 1.80-1.95 (1H, m),hydroxycyclobutyl)ethylamino)- 1.95-2.10 (3H, m), 4.1-4.4 (2H, m),4-(5-(trifluoromethyl)-1H- 4.90 (1H, br s), 7.20-7.90 (2H, m),pyrrolo[2,3-b]pyridin-3- 8.35 (2H, d), 8.95 (2H, s)yl)pyrimidine-5-carbonitrile 270 2-((S)-1-((1s,3R)-3- 403 1.05-1.20 (4H,m), 1.40-1.60 (2H, hydroxycyclobutyl)ethylamino)- m), 1.80-2.00 (1H, m),4-(5-(trifluoromethyl)-1H- 2.20-2.35 (3H, m), 3.80-3.90 (1H, m),pyrrolo[2,3-b]pyridin-3- 4.0-4.15 (1H, m), 4.85-4.95 (1H, d),yl)pyrimidine-5-carbonitrile 8.45-8.65 (2H, m), 8.70-8.80 (1H, m), 9.10(1H, s) 271 2-(1-(6-((R)-1- 509 1.56 (3H, d), 1.99 (1H, m), 2.33 (2H,methylpyrrolidin-3- m), 2.80-3.17 (4H, m), yloxy)pyridin-3- 5.27-5.41(2H, m), 6.79 (1H, t), 7.78 (1H, m), yl)ethylamino)-4-(5- 8.13-8.20 (1H,m), 8.71-8.82 (4H, (trifluoromethyl)-1H- m), 8.96-9.18 (1H, m), 13.05(1H, m) pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-5-carbonitrile 2722-(1-(6-((R)-pyrrolidin-3- 494 1.52 (3H, d), 1.91-2.15 (1H, m),ylamino)pyridin-3- 2.50-2.71 (1H, m), 2.72-3.3.15 (3H,yl)ethylamino)-4-(5- m), 3.20-3.58 (1H, m), (trifluoromethyl)-1H-4.08-4.22 (1H, m), 5.10-5.27 (1H, m), pyrrolo[2,3-b]pyridin-3- 6.38-6.55(2H, m), 7.35-7.50 (1H, m), yl)pyrimidine-5-carbonitrile 7.88-8.05 (1H,m), 8.42-8.80 (4H, m), 9.05 + 9.17 (1H, 2 × s) 273 2-((R)-1-(6-((S)-3-508 1.2-1.3 (3H, m), 1.5-1.6 (3H, m), methylpiperazin-1-yl)pyridin-2.8-2.9 (1H, m), 3.0-3.13 (2H, m), 3-yl)ethylamino)-4-(5- 3.2-3.4 (2H,m), 4.22-4.35 (2H, m), (trifluoromethyl)-1H- 5.2-5.3 (1H, m), 6.87-7.0(1H, m), pyrrolo[2,3-b]pyridin-3- 7.65-7.75 (1H, m), 8.15-8.25 (1H, m),yl)pyrimidine-5-carbonitrile 8.55-8.8 (4H, m), 8.9-9.0 (1H, m), 9.08(0.6H, s), 9.18 (0.4H, s), 13.1-13.2 (1H, m) 274 2-((R)-1-(6-((R)-3- 5081.2-1.3 (3H, m), 1.5-1.6 (3H, m), methylpiperazin-1-yl)pyridin- 2.8-2.9(1H, m), 3.0-3.13 (2H, m), 3-yl)ethylamino)-4-(5- 3.2-3.4 (2H, m),4.22-4.35 (2H, m), (trifluoromethyl)-1H- 5.2-5.3 (1H, m), 6.87-7.0 (1H,m), pyrrolo[2,3-b]pyridin-3- 7.65-7.75 (1H, m), 8.15-8.25 (1H, m),yl)pyrimidine-5-carbonitrile 8.55-8.8 (4H, m), 8.9-9.0 (1H, m), 9.08(0.6H, s), 9.18 (0.4H, s), 13.1-13.2 (1H, m) 275 2-((R)-1-(6-(methyl(2-496 1.5-1.6 (3H, m), 2.5-2.6 (3H, m), (methylamino)ethyl)amino)pyridin-2.9-3.0 (3H, m), 3.07-3.12 (2H, m), 3-yl)ethylamino)-4-(5- 3.7-3.8 (2H,m), 5.25-5.35 (1H, m), (trifluoromethyl)-1H- 6.7-6.85 (1H, m), 7.7-7.82(1H, m), pyrrolo[2,3-b]pyridin-3- 8.07-8.15 (1H, m), 8.32-8.47 (2H, m),yl)pyrimidine-5-carbonitrile 8.7-8.84 (4H, m), 9.1 (0.6H, s), 9.2 (0.4H,s), 13.05-13.1 (1H, m) 276 2-((R)-1-(6-((3S,5R)-3,5- 522 1.2-1.3 (6H,m), 1.52-1.57 (3H, m), dimethylpiperazin-1- 2.68-2.72 (1H, m), 3.25-3.35(2H, yl)pyridin-3-yl)ethylamino)-4- m), 4.38-4.45 (2H, m),(5-(trifluoromethyl)-1H- 5.22-5.32 (1H, m), 6.9-7.0 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.65-7.75 (1H, m), 8.15 (0.6H, s), 8.25 (0.4H,yl)pyrimidine-5-carbonitrile s), 8.38-8.45 (1H, m), 8.7-8.82 (4H, m),8.9-9.0 (1H, m), 9.1 (0.6H, s), 9.2 (0.4H, s), 13.1-13.2 (1H, m) 2772-(1-(6-((S)-pyrrolidin-3- 494 1.52 (3H, d), 1.85-2.01 (1H, m),ylamino)pyridin-3- 2.51-2.65 (1H, m), 2.72-3.01 (3H,yl)ethylamino)-4-(5- m), 3.18-3-55 (1H, m), (trifluoromethyl)-1H-4.08-4.23 (1H, m), 5.12-5.30 (1H, m), pyrrolo[2,3-b]pyridin-3- 6.37-6.55(2H, m), 7.35-7.48 (1H, m), yl)pyrimidine-5-carbonitrile 7.90-8.05 (1H,m), 8.55-8.77 (4H, m), 9.05 + 9.16 (1H, 2 × s) 278 2-(1-(6-(2- 482 1.54(3H, m), 2.56 (3H, m), (methylamino)ethylamino)pyridin- 3.04-3.09 (2H,m), 3.46-3.52 (2H, m), 3-yl)ethylamino)-4-(5- 2.19 (1H, m), 6.63 (1H,m), (trifluoromethyl)-1H- 7.62 (1H, m), 7.96-8.04 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.40 (1H, m), 8.72 (4H, m),yl)pyrimidine-5-carbonitrile 9.03-9.18 (1H, m), 13.06-13.11 (1H, m) 2792-((1R)-1-(4-(1- 507 1.49-1.50 (4H, m), 2.11-2.40 (7H,methylpyrrolidin-3- m), 2.62-2.74 (1H, m), ylamino)phenyl)ethylamino)-3.72-3.88 (1H br, s), 5.20 (1H, m), 5.60 (1H, 4-(5-(trifluoromethyl)-1H-m), 6.46 (1.2H, d), 6.51 (0.8H, d), pyrrolo[2,3-b]pyridin-3- 7.10-7.14(2H, m), 8.67-8.74 (4H, yl)pyrimidine-5-carbonitrile m), 9.07 (0.6H, s),9.21 (0.4H, s) and 13.05 (1H, br s) 280 2-(1-(6-((S)-1- 508 2.08-2.40(4H, m), 2.45-2.55 (1H, m), methylpyrrolidin-3- 2.61-2.75 (1H, m),4.15-4.25 (1H, ylamino)pyridin-3- m), 5.12-5.22 (1H, m), 6.40-6.46 (1H,yl)ethylamino)-4-(5- dd), 6.56 (1H, t), 7.43 (1H, t),(trifluoromethyl)-1H- 7.92 + 8.00 (1H, 2 × s), 8.69-8.74 (4H,pyrrolo[2,3-b]pyridin-3- m), 9.07 + 9.19 (1H, 2 × s), 13.00 (1H,yl)pyrimidine-5-carbonitrile br s) 281 2-((R)-1-(4-(3- 496 (MeOH-d₄)1.62-1.75 (3H, m), (methylamino)propylamino)phenyl)ethylamino)- 2.0-2.1(2H, m), 2.7-2.8 (3H, m), 4-(5- 3.07-3.15 (2H, m), 3.4-3.55 (2H, m),(trifluoromethyl)-1H- 5.25-5.42 (1H, m), 7.03-7.1 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.85 (0.5H, s), 7.95 (0.5H, s),yl)pyrimidine-5-carbonitrile 8.0-8.1 (1H, m), 8.6-8.73 (2H, m), 8.8 (1H,s), 9.02 (1H, s), 9.42 (1H, s) 282 2-((R)-1-(6-((2- 510 1.2-1.3 (3H, m).1.5-1.6 (3H, m), (dimethylamino)ethyl)(methyl)amino)pyridin- 2.8 (3H,d), 2.92 (3H, d), 3.2-3.3 (2H, 3- m), 3.8-3.9 (2H, m), 5.2-5.35 (1H,yl)ethylamino)-4-(5- m), 6.65-6.8 (1H, m), 8.1-8.22 (1H,(trifluoromethyl)-1H- m), 8.7-8.85 (3H, m), 9.05-9.25 (1H,pyrrolo[2,3-b]pyridin-3- m), 9.3-9.55 (1H, m),yl)pyrimidine-5-carbonitrile 13.05-13.1 (1H, m) 283 2-((R)-1-(6-((3- 5251.25-1.35 (2H, m). 1.5-1.6 (3H, m),(dimethylamino)propyl)(methyl)amino)pyridin- 1.85-1.95 (3H, m), 2.74(3H, d), 3- 2.82 (3H, d), 2.95-3.1 (4H, m), yl)ethylamino)-4-(5-3.55-3.65 (2H, m), 5.2-5.3 (1H, m), (trifluoromethyl)-1H- 6.7-6.8 (1H,m), 7.7-7.8 (1H, m), pyrrolo[2,3-b]pyridin-3- 8.08-8.17 (1H, m),8.72-8.85 (3H, m), yl)pyrimidine-5-carbonitrile 9.1 (0.5H, s), 9.23(0.5H, s), 9.4-9.55 (1H, m), 13.05-13.15 (1H, m) 284 2-((R)-1-(6-(4- 536isopropylpiperazin-1- yl)pyridin-3-yl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 285 2-((R)-1-(6-(4-ethylpiperazin- 5221.2-1.28 (3H, m). 1.53-1.58 (3H, m), 1-yl)pyridin-3-yl)ethylamino)-2.95-3.1 (4H, d), 3.15-3.25 (2H, m), 4-(5-(trifluoromethyl)-1H- 3.5-3.6(2H, m), 5.22-5.32 (1H, m), pyrrolo[2,3-b]pyridin-3- 6.9-7.0 (1H, m),7.7-7.8 (1H, m), yl)pyrimidine-5-carbonitrile 8.18 (0.6H, m), 8.25(0.4H, s), 8.7-8.85 (3H, m), 9.05 (0.6H, s), 9.18 (0.4H, s), 9.4-9.55(1H, m), 13.05-13.1 (1H, m) 286 2-((R)-1-(6-((R)-3- 522 1.55 (3H, d),2.1-2.3 (2H, m), (dimethylamino)pyrrolidin-1- 2.8-2.9 (6H, m), 3.35-3.45(1H, m), yl)pyridin-3-yl)ethylamino)-4- 3.5-3.7 (2H, m), 3.75-4.0 (2H,m), (5-(trifluoromethyl)-1H- 5.25-5.35 (1H, m), 6.7-6.9 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.75-7.85 (0.55H, m), 7.85-7.95 (0.45H, m),yl)pyrimidine-5-carbonitrile 8.05 (0.55H, s), 8.15 (0.45H, s), 8.75-8.9(3H, m), 9.05 (0.5H, s), 9.18 (0.5H, s), 9.95-10.05 (1H, m), 13.05-13.1(1H, m) 287 2-((R)-1-(6-((2- 538 1.02 (3H, t). 1.1 (3H, t), 1.42 (3H,d), (diethylamino)ethyl)(methyl)amino)pyridin- 2.8-2.9 (3H, m),2.95-3.15 (6H, m), 3- 3.6-3.75 (2H, m), 5.1-5.2 (1H, m),yl)ethylamino)-4-(5- 6.6-6.7 (1H, m), 7.55-7.65 (1H, m),(trifluoromethyl)-1H- 7.95 (0.55H, s), 8.05 (0.45H, s),pyrrolo[2,3-b]pyridin-3- 8.6-8.72 (4H, m), 8.95 (0.55H, s),yl)pyrimidine-5-carbonitrile 9.1-9.2 (1H, m), 13.05-13.1 (1H, m) 2882-((R)-1-(6-((S)-1,3′- 548 bipyrrolidin-1′-yl)pyridin-3-yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 289 2-((R)-1-(6-(methyl(3- 510 0.8-0.9 (3H,m). 1.2-1.35 (2H, m), (methylamino)propyl)amino)pyridin- 1.85-2.0 (3H,m), 2.2-2.3 (1H, m), 3-yl)ethylamino)-4-(5- 2.35-2.5 (2H, m), 2.8-3.0(2H, m), (trifluoromethyl)-1H- 4.45-4.6 (1H, m), 6.35-6.45 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.2-7.35 (2H, m), 7.7-7.85 (2H, m),yl)pyrimidine-5-carbonitrile 8.0 (1H, s), 8.25 (0.5H, m), 8.6 (0.5H, s)290 2-((R)-1-(6-((S)-3- 522 1.55 (3H, d), 2.2-2.35 (2H, m),(dimethylamino)pyrrolidin-1- 2.8-2.9 (6H, m), 3.4-3.75 (3H, m),yl)pyridin-3-yl)ethylamino)-4- 3.75-4.0 (2H, m), 5.25-5.35 (1H, m),(5-(trifluoromethyl)-1H- 6.7-6.9 (1H, m), 7.75-7.85 (0.55H, m),pyrrolo[2,3-b]pyridin-3- 7.85-7.95 (0.45H, m), 8.05 (0.55H,yl)pyrimidine-5-carbonitrile s), 8.15 (0.45H, s), 8.75-8.9 (3H, m), 9.05(0.5H, s), 9.18 (0.5H, s), 9.95-10.05 (1H, m), 13.05-13.1 (1H, m) 2912-((R)-1-(6-((S)- 534 1.55 (3H, d), 1.8-2.2 (4H, m),hexahydropyrrolo[1,2- 3.0-3.08 (1H, m), 3.3-3.4 (1H, m),a]pyrazin-2(1H)-yl)pyridin-3- 3.5-3.8 (2H, m), 3.8-3.95 (1H, m),yl)ethylamino)-4-(5- 5.25-5.35 (1H, m), 6.85-7.0 (1H, m),(trifluoromethyl)-1H- 7.7-7.8 (1H, m), 8.15 (0.65H, d),pyrrolo[2,3-b]pyridin-3- 8.25 (0.35H, d), 8.75-8.9 (3H, m),yl)pyrimidine-5-carbonitrile 9.05 (0.6H, s), 9.18 (0.4H, s), 9.7-9.8(0.5H, m), 10.07-10.12 (0.5H, m), 13.05-13.1 (1H, m) 2922-((R)-1-(6-(4-methyl-1,4- 522 1.55 (3H, d), 2.1-2.2 (2H, m),diazepan-1-yl)pyridin-3- 2.7-2.8 (1.5H, m), 3.08-3.2 (1.5H, m),yl)ethylamino)-4-(5- 3.45-3.65 (4H, m), 4.2-4.33 (1H, m),(trifluoromethyl)-1H- 5.25-5.35 (1H, m), 6.75-6.9 (1H, m),pyrrolo[2,3-b]pyridin-3- 7.7-7.85 (1H, m), 8.12 (0.5H, s),yl)pyrimidine-5-carbonitrile 8.2 (0.5H, s), 8.75-8.9 (3H, m), 9.15(0.5H, s), 9.23 (0.5H, s), 9.5-9.65 (1H, m), 10.05-10.15 (1H, m) 2932-(1-(6-((R)-1- 508 1.54 (3H, d), 1.85-2.10 (1H, br s),methylpyrrolidin-3- 2.80-2.95 (4H, m), 3.47 (4H, maskedylamino)pyridin-3- by water peak), 4.30-4.50 (1H, br s),yl)ethylamino)-4-(5- 5.15-5.30 (1H, br s), 6.55-6.75 (1H,(trifluoromethyl)-1H- m), 7.55-7.75 (1H, m), pyrrolo[2,3-b]pyridin-3-8.70-8.80 (4H, m), 9.05-9.20 (2 × 0.5H, 2 s),yl)pyrimidine-5-carbonitrile 9.65-10.0 (1H, br m), 13.10 (1H, d) 2942-((R)-1-(6-(4- 536 1.45-1.6 (6H, m), 1.95-2.1 (3H, m),(dimethylamino)piperidin-1- 2.7-2.9 (8H, m), 3.3-3.4 (1H, m),yl)pyridin-3-yl)ethylamino)-4- 4.4-4.5 (2H, m), 5.2-5.3 (1H, m),(5-(trifluoromethyl)-1H- 6.93-7.05 (1H, m), 7.65-7.79 (1H, m),pyrrolo[2,3-b]pyridin-3- 8.05 (0.55H, s), 8.15 (0.45H, s),yl)pyrimidine-5-carbonitrile 8.72-8.9 (4H, m), 9.05 (0.5H, s), 9.18(0.5H, s), 9.4-9.55 (1H, m), 13.05-13.1 (1H, m) 2952-((1R)-1-(6-(methyl(1- 522 / methylpyrrolidin-3- yl)amino)pyridin-3-yl)ethylamino)-4-(5- (trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 296 2-((R)-1-(6-((2- 524 /(dimethylamino)ethyl)(ethyl)amino)pyridin- 3- yl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 297 2-((R)-1-(6-(1- 522 /methylpiperidin-4- ylamino)pyridin-3- yl)ethylamino)-4-(5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 298 2-((R)-1-(6-((R)- 534 1.55 (3H, d),1.8-2.2 (4H, m), hexahydropyrrolo[1,2- 3.0-3.08 (1H, m), 3.3-3.4 (1H,m), a]pyrazin-2(1H)-yl)pyridin-3- 3.5-3.8 (2H, m), 3.8-3.95 (1H, m),yl)ethylamino)-4-(5- 4.45-4.55 (0.5H, m), 4.65-4.75 (0.5H, m),(trifluoromethyl)-1H- 5.25-5.35 (1H, m), 6.85-7.02 (1H,pyrrolo[2,3-b]pyridin-3- m), 7.68-7.78 (1H, m), 8.15 (0.6H,yl)pyrimidine-5-carbonitrile d), 8.25 (0.4H, d), 8.75-8.9 (3H, m), 9.05(0.6H, s), 9.18 (0.4H, s), 9.68-9.8 (0.5H, m), 10.07-10.15 (0.5H, m),13.05-13.15 (1H, m) 299 2-((R)-1-(2-(4- 509 1.52-1.56 (3H, m), 2.2 (3H,d), methylpiperazin-1- 2.3-2.4 (4H, m), 3.65-3.75 (4H, m),yl)pyrimidin-5-yl)ethylamino)- 5.1-5.22 (1H, m), 8.38-8.47 (1H, m),4-(5-(trifluoromethyl)-1H- 8.72-8.8 (4H, m), 9.02 (0.5H, s),pyrrolo[2,3-b]pyridin-3- 9.15 (0.5H, s), 13.05-13.1 (1H, m)yl)pyrimidine-5-carbonitrile 300 2-(I-1-(6-(I-1- 509 1.56 (3H, d),1.99-2.30 (2H, m), methylpyrrolidin-3- 2.81-2.91 (3H, m), 3.10-3.27 (1H,yloxy)pyridin-3- m), 3.64-3.75 (2H, m), yl)ethylamino)-4-(5- 5.27-5.36(1H, m), 5.51-5.55 (1H, m), (trifluoromethyl)-1H- 6.80 (1H, t), 7.79(1H, m), pyrrolo[2,3-b]pyridin-3- 8.13-8.22 (1H, m), 8.71-8.86 (4H, m),yl)pyrimidine-5-carbonitrile 8.96-9.18 (1H, m), 10.01 (1H, m), 13.08(1H, m) 301 2-((S)-1-(6-(I-1- 509 1.56 (3H, d), 1.99-2.30 (2H, m),methylpyrrolidin-3- 2.81-2.91 (3H, m), 3.10-3.27 (1H, yloxy)pyridin-3-m), 3.67 (2H, m), 5.27-5.35 (1H, yl)ethylamino)-4-(5- m), 5.51-5.55 (1H,m), 6.83 (1H, (trifluoromethyl)-1H- t), 7.79 (1H, m), 8.14-8.22 (1H,pyrrolo[2,3-b]pyridin-3- m), 8.72-8.86 (4H, m),yl)pyrimidine-5-carbonitrile 8.96-9.18 (1H, m), 10.01 (1H, m), 13.08(1H, m) 302 2-(I-1-(2-hydroxypyrimidin- 427 (MeOH-d₄) 1.65-1.75 (3H, m),5-yl)ethylamino)-4-(5- 5.1-5.2 (0.8H, m), 5.3-5.4 (0.6H,(trifluoromethyl)-1H- m), 8.42-8.55 (2H, m), pyrrolo[2,3-b]pyridin-3-8.6-8.7 (2H, m), 8.82 (1H, s), 9.15 (0.4H, yl)pyrimidine-5-carbonitriles), 9.4 (0.6H, s) 303 2-(I-1-(2-methoxypyrimidin- 441 1.62-1.68 (3H, m),3.87-3.92 (3H, 5-yl)ethylamino)-4-(5- m), 5.26-5.32 (1H, m),(trifluoromethyl)-1H- 8.42-8.55 (2H, m), 8.62 (1H, s), 8.7-8.8 (4H,pyrrolo[2,3-b]pyridin-3- m), 8.82 (1H, d), 8.9 (0.6H, s),yl)pyrimidine-5-carbonitrile 9.2 (0.4H, s), 15.1-15.2 (1H, m) 3042-((R)-1-(4-((2- 509 1.48-1.52 (3H, m), 2.13-2.16 (6H,(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)- m), 2.25-2.40(2H, m), 4-(5-(trifluoromethyl)-1H- 2.80-2.87 (3H, m), 3.33-3.55 (3H,m), pyrrolo[2,3-b]pyridin-3- 6.56-6.66 (2H, m), 7.15-7.25 (2H, m),yl)pyrimidine-5-carbonitrile 8.65-8.75 (4H, m), 9.05 + 9.21 (1H, 2 × s),13.02 (1H, br s)

Preparation 4:2-(4-chloro-5-cyanopyrimidin-2-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide

2,4-dichloropyrimidine-5-carbonitrile (E. F. Godefroi, J. Org. Chem.,1962, 27(6), 2264-6) (0.10 g, 0.57 mmol),2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide.1TFA (Meinke, PeterT.; Shih, Thomas L.; Fisher, Michael H., U.S. Pat. No. 6,221,894 B1)(0.171 g, 1.14 mmol) and DIPEA (0.39 mL, 2.29 mmol) were combined inanhydrous THF (5 mL) in a sealed tube and heated to 90° C. for 18 hours,before cooling to room temperature. The solvent was evaporated in vacuoand the residue purified by flash chromatography (40 g SiO₂,pentane/ethyl acetate, 30-70% over 14 column volumes) to afford thetitle compound as a colorless waxy solid (0.036 g, 19.7%).

MS (ES+): 322.28.

MS (ES−): 320.39.

Example 52-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamideStep 1:2-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)₂-methyl-N-(2,2,2-trifluoroethyl)propanamide

A mixture of5-trifluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(23 mg, 0.07 mmol, 1.0 Eq.) and2-(4-chloro-5-cyanopyrimidine-2-ylamino)-2-methyl-N-(2,2,2-trifluoromethyl)propanamide(33 mg, 0.07 mmol, 1.0 Eq.) was suspended in toluene (2.0 mL) and EtOH(0.5 mL) and treated with 2M K₂CO₃ (105 ul, 0.21 mmol, 3.0 Eq.). Themixture was sonicated under an atmosphere of nitrogen for 20 minutes andthen treated with Pd(PPh₃)₄ (8 mg, 0.007 mmol, 0.1 Eq.). Aftersonication for a further 5 minutes the reaction was heated undermicrowave conditions at 140° C. for 20 minutes. The reaction waspartitioned between EtOAc and water and the aqueous phase extracted withEtOAc (3×). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/PetroleumEther) to give the title compound as a white solid (29 mg, 66%).

Step 2:2-(5-cyano-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide

2-(5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamino)₂-methyl-N-(2,2,2-trifluoroethyl)propanamide(29 mg, 0.046 mmol, 1.0 Eq.) was dissolved in THF (4 mL) and water (1mL) and treated with LiOH.H₂O (10 mg, 0.23 mmol, 15 eq) and allowed tostir at room temperature overnight. The reaction mixture wasconcentrated and the residue partitioned between EtOAc and water. Theorganic phase was washed with saturated aqueous NaHCO₃ followed bybrine, dried over MgSO₄, filtered and the solvent evaporated. Theresidue was purified by column chromatography (ISCO Companion™, 12 gcolumn, 0-100% EtOAc/Petroleum Ether) to give the title compound as awhite solid (13 mg, 60%). MS (ES⁺) m/e=472. ¹H NMR (DMSO) 1.53 (6H, s),1.58 (6H, s), 3.65-3.69 (2H, m), 3.75-3.79 (2H, m), 8.26-8.34 (2H, m),8.45 (1H, s), 8.65-8.78 (6H, m), 8.96 (1H, s), 9.29 (1H, s), 13.05 (2H,brs) [1:1 Mixture of rotamers]

A variety of other compounds of Formula I have been prepared by themethods of Example 5. The characterization data for these compounds issummarized in Table II-B below and includes LC/MS (observed) and ¹H NMRdata.

TABLE II-B M + 1 Compound No. Name (obs) ¹H NMR IA-1 2-(5-cyano-4-(5-486 (DMSO) 1.51 (6H, s), 1.56 (6H, s), (trifluoromethyl)-1H- 1.76-1.91(2H, m), 2.01-2.39 (2H, pyrrolo[2,3-b]pyridin-3- m), 3.06 (2H, brq),3.24 (2H, brq), yl)pyrimidin-2-ylamino)-2- 7.90 (2H, t), 8.33 (1H, s),8.42 (1H, methyl-N-(3,3,3- s), 8.70-8.77 (6H, m), 8.99 (1H, s),trifluoropropyl)propanamide 9.28 (1H, s), 13.04 (1H, brs). [1:1 Mixtureof rotamers.] IA-2 1-(4-(5-chloro-1H-pyrrolo[2,3- 452 (DMSO) 1.54 (6H,d), 2.10 (1H, m), b]pyridin-3-yl)-5- 2.35 (1H, m), 3.25 (2H, m), 6.56cyanopyrimidin-2-ylamino)-N- (1H, br s), 7.90 (1H, m), 8.38 (2H, (2,2,2-m), 8.66 (2H, m), 9.20 (1H, d), 12.80 trifluoroethyl)cyclohexane- (1H,s) carboxamide IA-3 1-(4-(5-chloro-1H-pyrrolo[2,3- 478b]pyridin-3-yl)-5- cyanopyrimidin-2-ylamino)-N- (2,2,2-trifluoroethyl)cyclohexane- carboxamide478 IA-42-(4-(5-chloro-1H-pyrrolo[2,3- 424 b]pyridin-3-yl)-5-cyanopyrimidin-2-ylamino)-N- cyclopentyl-2- methylpropanamide IA-52-(4-(5-chloro-1H-pyrrolo[2,3- 438 b]pyridin-3-yl)-5-cyanopyrimidin-2-ylamino)-N- cyclohexyl-2- methylpropanamide IA-6(2S)-2-(4-(5-chloro-1H- 424 (DMSO) 1.47 (3H, m), 3.81 (3H, m),pyrrolo{2,3-b]pyridin-3-yl)-5- 7.53 (1H, m), 8.20 (1H, s), 8.26 (2H,cyanopyrimidin-2-ylamino)-N- br s), 8.43 (1H, s), 8.57 (1H, s), 8.65(2,2,2- (1H, s), 8.97 (1H, s) trifluoroethyl)propanamide IA-71-(4-(5-chloro-1H-pyrrolo[2,3- 464 (MeOD) 1.87 (4H, br s), 2.20 (2H,b]pyridin-3-yl)-5- m), 2.45 (2H, m), 3.83 (2H, m), 8.29cyanopyrimidin-2-ylamino)-N- (1H, s), 8.41 (2H, m), 8.52 (1H, s),(2,2,2- 8.72 (1H, s), 8.83 (1H, s), 9.30 (1H, s)trifluoroethyl)cyclopentane- carboxamide IA-82-(4-(5-chloro-1H-pyrrolo[2,3- 370 (MeOD/CDCl3) 1.63 (6H, br s), 2.71b]pyridin-3-yl)-5- (3H, m), 8.29 (1H, s), 8.54 (1H, s),cyanopyrimidin-2-ylamino)- 8.69 (1H, s), 9.25 (1H, br s)N,2-dimethylpropanamide IA-9 2-(5-cyano-4-(5- 391 (MeOD) 1.58 (3H, s),1.67 (3H, s), (trifluoromethyl)-1H- 8.49 (1H, s), 8.55 (1H, s), 8.70(1H, pyrrolo[2,3-b]pyridin-3- s), 9.13 (1H, s), 9.31 (1H, s)yl)pyrimidin-2-ylamino)-2- methylpropanoic acid IA-102-(5-cyano-4-(1H-pyrrolo[2,3- 404 (MeOD) 1.64 (br, 6H), 3.80 (br, 2H),b]pyridin-3-yl)pyrimidin-2- 7.37 (s, 1H), 8.58-8.36 (m, 2.78H),ylamino)-2-methyl-N-(2,2,2- 8.69 (br, 1H), 8.92 (br, 0.44H), 9.30trifluoroethyl)propanamide (br, 0.47H) IA-112-(4-(5-chloro-1H-pyrrolo[2,3- 438 (CD3OD/CDCl3) 1.64 (6H, s), 3.82b]pyridin-3-yl)-5- (2H, m), 7.60 (1H, br s), 8.25 (1H,cyanopyrimidin-2-ylamino)-2- s), 8.47 (1H, s), 8.64 (1H, s), 8.75methyl-N-(2,2,2- (1H, br s), 8.99 (1H, br s) trifluoroethyl)propanamideIA-12 (2R)-2-(5-cyano-4-(5- 420 1.42 (3H, m), 3.13 (2H, m), 3.46(trifluoromethyl)-1H- masked signal, 4.54-4.58 (2H, m),pyrrolo[2,3-b]pyridin-3- 7.84-8.03 (1H, m), 8.23-8.61 (1H,yl)pyrimidin-2-ylamino)-N-(2- m), 8.70-8.76 (3H, m), 8.93-9.30hydroxyethyl)-propanamide (1H, m), 13.07 (1H, m) rotamers observed IA-13(2R)-2-(5-cyano-4-(5- 460 1.24-1.44 (7H, m), 1.76-1.99 (2H,(trifluoromethyl)-1H- m), 3.77-3.83 (2H, m), 4.54-4.72pyrrolo[2,3-b]pyridin-3- (2H, m), 7.91-8.12 (1H, m), 8.57-yl)pyrimidin-2-ylamino)-N-(2- 8.82 (4H, m), 8.96-9.30 (1H, m),hydroxycyclopentyl)propanamide 13.07 (1H, m) rotamers observed IA-142-(5-cyano-4-(5- 434 0.84 (6H, m), 2.34 (2H, m), 2.75(trifluoromethyl)-1H- (2H, m), 7.06 (1H, br s), 7.78 (2H,pyrrolo[2,3-b]pyridin-3- m), 7.99 (1H, s), 8.30-8.61 (1H, m)yl)pyrimidin-2-ylamino)-N-(2- hydroxyethyl)-2- methylpropanamide

Example 62-(phenylthio)-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(75 mg, 0.15 mmol) was heated with benzenethiol (31 uL, 0.30 mmol, 2.0Eq.) and DIPEA (78 uL, 0.45 mmol, 3.0 Eq.) in THF (2 mL) under microwaveconditions at 100° C. for 10 minutes. A solution of LiOH.H₂O (32 mg,0.75 mmol, 5.0 Eq.) in water (1 mL) was added to the mixture and thereaction left to stir for 90 minutes. The reaction was partitionedbetween EtOAc and water and the aqueous phase extracted with EtOAc. Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The resultant solid was purified by column chromatography (ISCOCompanion™, 12 g column, 0-30% EtOAc/Petroleum Ether) and lyophilized togive the title compound as a pale yellow solid (28 mg, 47% over 2steps).

MS (ES⁺) m/e=398. ¹H NMR (DMSO) 7.48-7.50 (3H, m), 7.68-7.71 (2H, m),8.37 (1H, s), 8.70 (1H, s), 8.80 (1H, s), 9.02 (1H, s), 13.25 (1H, brs).

Other compounds of Formula I prepared by the methods of Example 3 areillustrated in Table III-A. The characterization data for thesecompounds is summarized in Table III-B below and includes LC/MS(observed) and ¹H NMR data.

TABLE III-A

II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-0

TABLE IIIB Compound No M + 1 ¹H NMR (II-) Name (obs) (DMSO-D₆ Exceptwhere noted) 1 2-(methylthio)-4-(5- 336 2.70 (3H, s), 8.79 (1H, s), 8.85(1H, s), (trifluoromethyl)-1H-pyrrolo[2,3- 9.04 (1H, s), 9.13 (1H, s),13.32 (1H, b]pyridin-3-yl)pyrimidine-5- brs). carbonitrile 22-(4-chlorophenylthio)-4-(5- 432 7.55 (2H, d), 7.74 (2H, d), 8.39 (1H,s), (trifluoromethyl)-1H-pyrrolo[2,3- 8.81 (1H, s), 8.83 (1H, s), 9.04(1H, s), b]pyridin-3-yl)pyrimidine-5- 13.30 (1H, brs). carbonitrile 32-(4-methoxyphenylthio)-4-(5- 428 3.80 (3H, s), 7.03 (2H, d), 7.60 (2H,d), (trifluoromethyl)-1H-pyrrolo[2,3- 8.40 (1H, s), 8.71 (1H, s), 8.81(1H, s), b]pyridin-3-yl)pyrimidine-5- 9.02 (1H, s), 13.28 (1H, brs).carbonitrile 4 2-(3-bromophenylthio)-4-(5- 476 7.45 (1H, t), 7.71 (2H,t), 7.92 (1H, s), (trifluoromethyl)-1H-pyrrolo[2,3- 8.39 (1H, s), 8.69(1H, s), 8.86 (1H, s), b]pyridin-3-yl)pyrimidine-5- 9.01 (1H, s), 13.32(1H, brs). carbonitrile 5 2-(2-chlorophenylthio)-4-(5- 432 7.47 (1H, t),7.56 (1H, t), 7.67 (1H, d), (trifluoromethyl)-1H-pyrrolo[2,3- 7.89 (1H,d), 8.35 (1H, s), 8.72 (1H, s), b]pyridin-3-yl)pyrimidine-5- 8.81 (1H,s), 9.06 (1H, s), 13.31 (1H, carbonitrile brs). 62-(3-chlorophenylthio)-4-(5 - 432 (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5- carbonitrile 7 2-(2-bromophenylthio)-4-(5-476 7.27 (2H, m), 7.63 (1H, d), 7.70 (1H, d),(trifluoromethyl)-1H-pyrrolo[2,3- 8.14 (1H, s), 8.49 (1H, s), 8.61 (1H,s), b]pyridin-3-yl)pyrimidine-5- 8.84 (1H, s) carbonitrile 82-(4-bromophenylthio)-4-(5- 476 (trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5- carbonitrile 9 2-(3-ethoxyphenylthio)-4-(5-442 (trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidine-5-carbonitrile 10 2-(phenethylthio)-4-(5- 426(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidine-5-carbonitrile 11 2-(3-methoxyphenylthio)-4-(5- 428(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidine-5-carbonitrile 12 2-(isopropylthio)-4-(5- 364 1.45 (6H, d), 4.07 (1H, m),8.79 (1H, s), (trifluoromethyl)-1H-pyrrolo[2,3- 8.85 (1H, s), 9.04 (2H,m), 13.32 (1H, s) b]pyridin-3-yl)pyrimidine-5- carbonitrile 132-(cyclohexylthio)-4-(5- 404 1.44 (8H, m), 2.09 (2H, m), 3.91 (1H,(trifluoromethyl)-1H-pyrrolo[2,3- m), 8.79 (2H, d), 9.00 (2H, d), 13.31b]pyridin-3-yl)pyrimidine-5- (1H, s) carbonitrile 142-(2-methoxyphenylthio)-4-(5- 428 3.71 (3H, s), 7.05 (1H, t), 7.16 (1H,d), (trifluoromethyl)-1H-pyrrolo[2,3- 7.51 (1H, t), 7.64 (1H, d), 8.40(1H, s), b]pyridin-3-yl)pyrimidine-5- 8.74 (1H, d), 8.80 (1H, d), 8.99(1H, s), carbonitrile 13.31 (1H, s) 15 2-(1-hydroxyhexan-3-ylthio)-4-422 (5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile 16 2-(pentan-2-ylthio)-4-(5- 392(MeOD/CDCl₃) 0.97 (6H, d), 1.69 (2H, (trifluoromethyl)-1H-pyrrolo[2,3-m), 1.80 (1H, m), 3.36 (2H, m), 8.65 b]pyridin-3-yl)pyrimidine-5- (1H,s), 8.75 (1H, s), 8.87 (1H, s), 9.20 carbonitrile (1H, s) 172-(phenylthio)-4-(5- 398 7.48-7.50 (3H, m), 7.68-7.71 (2H, m),(trifluoromethyl)-1H-pyrrolo[2,3- 8.37 (1H, s), 8.70 (1H, s), 8.80 (1H,s), b]pyridin-3-yl)pyrimidine-5- 9.02 (1H, s), 13.25 (1H, brs)carbonitrile

Using the methods of Example 3, compounds wherein R² is −OR⁶ wereprepared as follows.

Example 72-Phenoxy-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

MS (ES⁺) m/e=382. ¹H NMR (DMSO) 7.4-7.45 (3H, m), 7.48-7.53 (2H, m), 8.3(1H, s), 8.72 (1H, s), 8.9 (1H, s), 9.23 (1H, s)

Example 82-isopropoxy-4-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

MS (ES⁺) m/e=349. ¹H NMR (MeOH) 1.55 (6H, d), 5.55 (1H, m), 8.95 (1H,s), 8.9 (1H, s), 8.97 (1H, s), 9.32 (1H, s)

Example 92-(isopropylamino)-4-(5-(phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Step 1: 1H-pyrrolo[2,3-b]pyridin-5-amine

5-bromo-1H-pyrrolo[2,3-b]pyridine (6.0 g, 30.45 mmol) in ammoniumhydroxide (120 mL) was treated with copper sulphate pentahydrate (1.50g, 6.09 mmol, 0.2 eq) and heated in a sealed tube overnight. Thereaction was diluted with EtOAc and the insoluble black solid wasfiltered off. The filtrate was extracted (EtOAc/Water) and the organiclayer washed with saturated aqueous ammonium chloride, followed by waterand brine. The organics were dried over magnesium sulphate, filtered andevaporated to dryness to give the product as a pale brown solid (2.57 g,63%)

Step 2: Benzyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

1H-pyrrolo[2,3-b]pyridin-5-amine (9.45 g, 71.05 mmol) was dissolved inTHF (150 mL) and stirred at 0° C. under an atmosphere of nitrogen.Benzyl chloroformate (20.3 mL, 142.10 mmol, 2.0 Eq) was added dropwiseover a period of 15 minutes and the mixture allowed to stir at roomtemperature for 30 minutes. The mixture was treated with 4M NaOH (aq)(53.3 mL, 213.16 mmol, 3.0 Eq) over a period of 15 minutes and theresultant brown solution left to stir for 16 hours. The reaction mixturewas taken to pH 4 (125 mL of 10% aq. citric acid) and the 2 layers wereseparated. The aqueous layer was back extracted with EtOAc and thecombined organics were dried over magnesium sulphate, filtered and driedunder vacuum. The crude product was purified by column chromatography(50% EtOAc/Petroleum Ether) to give 14.59 g (77%) of pale yellow solid.

Step 3: Benzyl 3-bromo-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (9.48 g, 35.5 mmol) inchloroform (100 mL) was cooled to 5° C. and treated dropwise withbromine (1.86 mL, 36.21 mmol, 1.02 Eq). The reaction was allowed to tostir at 0° C. for 1 hour and then at room temperature for 1 hour. Themixture was diluted with DCM and washed with a 1:1 sat. aq. sodiumthiosulfate/sodium bicarbonate solution (200 mL). The organic layer wasseparated and the aqueous layer taken to pH 12 and re-extracted withEtOAc. The combined organics were dried over magnesium sulphate,filtered and dried under vacuum and the resultant brown solid trituratedwith diethyl ether/EtOAc to give 10.24 g (83%) of the title compound.

Step 4: Benzyl 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl 3-bromo-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (10.22 g, 29.53mmol) in dry THF (120 mL) was cooled to 0° C. and treated portionwisewith sodium hydride (1.193 g, 29.83 mmol, 1.01 Eq). The mixture wasallowed to stir at this temperature for 1 hour and then treated withtosyl chloride (5.744 g, 30.13 mmol, 1.02 Eq) in THF (15 mL) over aperiod of 10 minutes. The mixture was left to stir at room temperaturefor a further 4 hours and then quenched with sat. aq. ammonium chloride.The mixture was diluted with EtOAc and the organic layer separated,washed with brine, dried over magnesium sulphate, filtered andevaporated to dryness. The crude product was purified by columnchromatography (5% MeOH/DCM) to give 11.09 g (75%) of brown solid.

Step 5: Benzyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (3.51 g,7.02 mmol) in dry dioxane (35 mL) was treated withbis(pinacolato)diboron (2.14 g, 8.42 mmol, 1.2 Eq) and potassium acetate(2.06 g, 98.15 mmol, 3.0 Eq), the reaction mixture was degassed andstirred under nitrogen for 20 minutes and then treated with Pd(PPh₃)₄(0.811 g, 0.70 mmol, 0.1 Eq). The mixture was degassed and heated atreflux under nitrogen for 2 hours. The mixture was partitioned betweenEtOAc and sat. aq ammonium chloride, the organic layer was separated,washed with brine, dried over magnesium sulphate and evaporated todryness. The residue was filtered through a plug of Florisil elutingwith 50% EtOAc/Petroleum ether and the resultant solid triturated withEtOAc to give the title compound as an off-white solid (2.805 g, 73%).

Step 6: Benzyl3-(5-cyano-2-(methylthio)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate(0.50 g, 0.91 mmol) in toluene/ethanol (7.5 mL:2.0 mL) was treated with4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.186 g, 1.00 mmol,1.1 Eq) and 2M aqueous potassium carbonate (1.37 mL, 2.74 mmol, 3.0 Eq),degassed and stirred under nitrogen for 20 minutes. Pd(dppf)₂Cl₂ (0.075g, 0.1 Eq) was added and the mixture allowed to heat at 100° C. for 1.5hours. The reaction was partitioned between EtOAc and saturated aqueoussodium carbonate and the organic layer separated, dried over magnesiumsulphate and evaporated to dryness. The mixture was purified by columnchromatography eluting with 10% EtOAc/Petroleum ether to yield a whitesolid (0.219 g, 42%).

Step 7: Benzyl3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl3-(5-cyano-2-(methylthio)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate(1.316 g, 2.308 mmol) in DCM (75 mL) was treated with mCPBA (0.877 g,5.08 mmol, 0.2 Eq) and allowed to stir at room temperature overnight.The mixture was evaporated to a smaller volume and the resultant solidfiltered off and washed with EtOAc (0.826 g, 60%).

Step 8: Benzyl3-(5-cyano-2-(isopropylamino)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate

Benzyl3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate(0.826 g, 1.372 mmol) in THF (30 mL) was treated with isopropylamine(0.234 mL, 2.744 mmol, 2.0 Eq) and DIPEA (0.478 mL, 2.744 mmol, 2.0 Eq)and allowed to heat at reflux for 1 hour. The mixture was concentratedin vacuo and purified by column chromatography (ISCO Companion™, 40 gcolumn, 0-100% EtOAc/Petroleum ether) to give 0.651 g (82%) of the titlecompound.

Step 9:4-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(isopropylamino)pyrimidine-5-carbonitrile

Benzyl3-(5-cyano-2-(isopropylamino)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate(0.199 g, 0.342 mmol) in EtOH (15 mL) was charged with ammonium formate(0.129 g, 2.055 mmol, 6.0 Eq) and 10% Pd/C (0.040 g, 0.2 Eq) and heatedat reflux for 3 hours.

Reaction mixture allowed to cool and filtered through a plug of celitewashing through with further EtOAc. The mixture was concentrated invacuo and purified by column chromatography (ISCO Companion™, 12gcolumn, 0-100% (EtOAc/Petroleum ether) to give the title compound as ayellow solid (0.103 g 67%).

Step 10:2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

4-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(isopropylamino)pyrimidine-5-carbonitrile(0.204 g, 0.455 mmol) in DCM (12 mL) was treated with phenylboronic acid(0.111 g, 0.910 mmol, 2.0 Eq), copper acetate (0.124 g, 0.682 mmol, 1.5Eq), pyridine (0.074 mL, 0.910 mmol, 2.0 Eq) and 4 Angstrom molecularsieves (0.600 g) and the reaction was allowed to stir at roomtemperature for 16 hours. The reaction mixture was quenched with 4MAmmonia in MeOH (12 mL) and filtered through a plug of celite whilstwashing through with further DCM/MeOH. The combined washes wereevaporated to dryness and purified by column chromatography (ISCOCompanion™, 12 g column, 0-100% EtOAc/Petroleum Ether) to give the titlecompound as a yellow solid (85 mg, 36%).

Step 11:2-(isopropylamino)-4-(5-(phenylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(0.083 g, 0.158 mmol) was stirred in THF (7 mL) and water (1.5 mL) andtreated with LiOH.H₂O (0.066 g, 1.60 mmol, 10.0 Eq) and allowed to stirat room temperature for 16 hours. The reaction mixture was concentratedand purified by column chromatography (50% EtOAc/Petroleum ether) toyield the product as a yellow solid (29 mg, 50%)

MS (ES⁺) m/e=370. ¹H NMR (DMSO) 1.12 (6H, m), 4.13 (1H, m), 6.79 (1H,m), 7.03 (2H, m), 7.22 (2H, m), 7.31 (1H), 8.19 (1H, m), 8.51 (2H, m),8.63 (1H, m), 11.98 (1H)

Example 103-(3-(5-cyano-2-(isopropylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)-N-methylbenzamide

The title compound prepared from4-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(isopropylamino)pyrimidine-5-carbonitrile using the methods described in Example 9.

MS (ES⁺) m/e=427. ¹H NMR (DMSO) 1.12 (6H, m), 2.80 (3H, m), 4.15 (1H,m), 7.12 (1H, m), 7.24 (3H, m), 7.53 (1H, m), 7.83 (2H, br s), 8.20 (1H,m), 8.52 (2H, m), 8.66 (1H, m), 12.00 (1H).

Example 112-((R)-1-hydroxy-3-methylbutan-2-ylamino)-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Step 1: 5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A solution of 5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (5 g, 14.29mmol), potassium trifluoro(methyl)borate (2.62 g, 21.43 mmol), cesiumcarbonate (12.56 g, 38.57 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.16 g,1.43 mmol) in THF (150 mL) and water (15 mL) was heated at reflux for 18hours. The reaction mixture was cooled down to ambient and partitionedbetween EtOAc (100 mL) and water (100 mL). The organic phase wasseparated, washed with 1N HCl (100 mL) and brine (100 mL), then, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified on silica gel by flash column chromatography to give the titlecompound as a white solid (1.903 g, 47% yield).

¹H NMR (DMSO-D₆, 400 MHz) δ 2.33 (3H, s), 2.34 (3H, s), 6.74 (1H, d),7.40 (2H, d), 7.83 (2H, s), 7.95 (2H, d), 8.20 (1H, s); MS (ES+) 287.

Step 2: 3-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.9 g, 6.62 mmol) indichloromethane (40 mL) was treated dropwise with a solution of bromine(0.678 mL, 13.24 mmol) in dichloromethane (3 mL). The resulting solutionwas stirred at room temperature for 3 hours. The reaction mixture waspartitioned between dichloromethane (150 mL) and a 1:1 mixture of asaturated aqueous solution of NaHCO3 and a saturated aqueous solution ofNa2S2O3 (250 mL). The organic phase was separated and the aqueous phasewas re-extracted twice with DCM (50 mL). The combined organic phaseswere dried over magnesium sulfate and concentrated in vacuo to give thedesired compound as an off-white solid (2.381 g, 99% yield). 1H NMR(DMSO-D₆, 400 MHz) δ 2.34 (3H, s), 2.39 (3H, s), 7.42 (2H, d), 7.75 (1H,s), 7.99 (2H, d), 8.14 (1H, s), 8.21 (1H, s); MS (ES+) 365.

Step 3:5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A mixture of 3-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.0 g,2.75 mmol), bis(pinacolato)diboron (1.046 g, 4.12 mmol) and potassiumacetate (0.851 g, 8.67 mmol) in dioxane (25 mL) was degassed and stirredunder nitrogen for 30 minutes. The reaction mixture was treated withtetrakis(triphenylphosphine)palladium(0) (0.317 g, 0.27 mmol) anddegassed again. The reaction mixture was then heated at reflux for 16hours. The resulting mixture was cooled down to room temperature andfiltered through a pad of celite washing with ethyl acetate. Thefiltrate was concentrated in vacuo and purified on florisil by flashcolumn chromatography to afford the title compound as a white solid(0.779 g, 69% yield).

¹H NMR (DMSO-D₆, 400 MHz) δ 1.32 (12H, s), 2.34 (3H, s), 2.37 (3H, s),7.42 (2H, d), 7.89 (1H, s), 7.99 (1H, s), 8.04 (2H, d), 8.22 (1H, s); MS(ES+) 413.

Step 4:4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile

A mixture of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(306 mg, 0.74 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile(207 mg, 1.12 mmol) in dioxane (9 mL) was degassed and stirred undernitrogen for 10 minutes. The reaction mixture was treated with potassiumcarbonate (336 mg, 2.23 mmol) and bis(tri-t-butylphosphine)palladium(0)(38 mg, 0.074 mmol) and degassed again. The reaction mixture and stirredunder nitrogen for 10 minutes. Water (1.35 mL) was added and thereaction mixture was degassed and stirred under nitrogen for 2 hours. Asuspension was observed. The resulting mixture was filtered and thesolid was washed with dioxane and water. The solid was dried in a vacuumoven to afford the title compound as a white solid (282 mg, 87% yield).

¹H NMR (DMSO-D₆, 400 MHz) δ 2.36 (3H, s), 2.42 (3H, s), 2.68 (3H, s),7.46 (2H, d), 8.07 (2H, d), 8.36 (1H, s), 8.49 (1H, s), 8.93 (1H, s),9.15 (1H, s); MS (ES+) 436.

Step 5:4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile

4-(5-Methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile(216 mg, 0.498 mmol) in dichloromethane (15 mL) was treated withm-chloroperbenzoic acid (215 mg, 1.244 mmol). The resulting suspensionwas allowed to stir at room temperature for 18 hours. The reactionmixture was partitioned between dichloromethane and a 1:1 mixture of asaturated aqueous solution of NaHCO3 and a saturated aqueous solution ofNa2S2O3 (50 mL). The organic phase was separated and the aqueous phasewas re-extracted twice with DCM. The combined organic phases were driedover magnesium sulfate and concentrated in vacuo. The resulting solidwas triturated with EtOH and filtered to afford the title compound as anoff-white solid (186 mg, 80% yield, 10:90 sulfoxide:sulfone mixture byLCMS).

¹H NMR (DMSO-D₆, 400 MHz) δ 2.37 (3H, s), 2.42 (3H, s), 3.54 (3H, s),7.48 (2H, d), 8.10 (2H, d), 8.40 (1H, s), 8.61 (1H, s), 9.09 (1H, s),9.64 (1H, s); MS (ES+) 468 (sulfone), (ES+) 452 (sulfoxide).

Step 6:2-((R)-1-hydroxy-3-methylbutan-2-ylamino)-4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

A mixture of4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile(120 mg, 0.257 mmol), (R)-(+2-amino-3-methyl-1-butanol (57 l, 0.515mmol) and diisopropylethylamine (90 l, 0.515 mmol) in THF (4 mL) washeated at reflux for 1 hour. The reaction mixture was concentrated invacuo and the residue was purified on silica gel by flash columnchromatography to give the title compound as a colourless glassy solid(97 mg, 77% yield).

¹H NMR (DMSO-D₆, 400 MHz) δ 0.92 (3H, d), 0.94 (3H, d), 1.98 (1H, m),2.36 (3H, s), 2.40 and 2.45 (3H, 2 s rotamers), 3.50-3.64 (2H, m), 3.97(1H, m), 4.68 (1H, dt), 7.45 (2H, d), 8.05 (2H, dd), 8.19 (1H, t), 8.33(1H, dd), 8.54 and 8.80 (1H, 2 br s rotamers), 8.73 and 8.76 (1H, 2 srotamers), 8.82 and 8.86 (1H, 2 s rotamers); MS (ES+) 491, (ES−) 489.

Step 7:2-((R)-1-hydroxy-3-methylbutan-2-ylamino)-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

2-((R)-1-Hydroxy-3-methylbutan-2-ylamino)-4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile(97 mg, 0.198 mmol) in THF (7 mL) and water (1.5 mL) was treated withlithium hydroxide monohydrate (83 mg, 1.98 mmol). The reaction mixturewas stirred at room temperature for 18 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated andthe aqueous phase was re-extracted twice with EtOAc and twice with DCM.The combined organic layers were dried over magnesium sulfate andconcentrated in vacuo. The residue was purified on silica gel by flashcolumn chromatography then via reverse phase preparative HPLC [WatersSunfire C18, 10 M, 100 Å column, gradient 10%-95% B (solvent A: 0.05%TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to affordthe title compound as an off-white solid and a TFA salt (12.5 mg, 14%yield).

¹H NMR (DMSO-D₆, 400 MHz) δ 0.94 (6H, m), 2.01 (1H, m), 2.05 (3H, s),3.59 (2H, m), 4.08 (1H, m), 4.68 (1H, m), 7.89 (1H, m), 8.21 (1H, m),8.51 (1H, m), 8.61 (2H, m), 8.87 (1H, s), 12.42 (1H, s); MS (ES+) 337,(ES−) 335

Example 12 PLK Assays

The compounds of the present invention are evaluated as inhibitors ofhuman PLK kinase using the following assays.

PLK1 Inhibition Assay I:

Compounds were screened for their ability to inhibit PLK1 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, and 1 mM DTT. Finalsubstrate concentrations were 350 μM [γ-33P]ATP (136 mCi 33P ATP/mmolATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 450 μM peptide(KKKISDELMDATFADQEAK) [SEQ. ID:1]. Assays were carried out at 25° C. inthe presence of 2 nM PLK1. An assay stock buffer solution was preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution wasplaced in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 350 μM).

The reaction was stopped after 240 minutes by the addition of 1000 μL,0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-wellplate (Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.1 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.1 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK1 Inhibition Assay II:

Compounds were screened for their ability to inhibit PLK1 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, 0.1% BSA, and 2 mM DTT.Final substrate concentrations were 150 μM [γ-33P]ATP (115 mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μMpeptide (KKKISDELMDATFADQEAK) [SEQ. ID:2]. Assays were carried out at25° C. in the presence of 4 nM PLK1. An assay stock buffer solution wasprepared containing all of the reagents listed above, with the exceptionof ATP and the test compound of interest. 30 μL of the stock solutionwas placed in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 150 μM).

The reaction was stopped after 90 minutes by the addition of 100 μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate(Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.1 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.1 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

The following table contains results for the compounds in these assays.In the table, PLK1 inhibition K_(i)<3 nM is +++, PLK1 inhibition K_(i)between 3 nM and 40 nM is ++, and PLK1 K_(i)>40 nM is +; NT means thecompound has not been evaluated.

IA-0 ++ IA-1 + I-1 + II-1 + I-2 + I-3 ++ I-4 + I-5 + I-6 +++ I-7 + I-8 +II-0 ++ IA-9 + I-9 ++ I-10 ++ I-11 + I-12 + I-13 + I-14 ++ I-15 + I-16++ I-17 + I-18 ++ I-19 + I-20 + I-21 + I-22 + I-23 + I-24 ++ I-25 ++II-2 + II-3 + II-4 + II-5 + II-6 + II-7 + II-8 + II-9 + II-10 + II-11 +I-26 +++ I-27 + II-12 + II-13 + I-28 + I-29 ++ II-14 + I-30 + I-31 ++I-32 + I-33 + I-34 + I-35 ++ I-36 ++ II-15 + I-37 + I-38 + I-39 ++I-40 + I-41 + I-42 + II-16 + I-43 + I-44 + I-45 ++ I-46 + I-47 +++I-48 + I-49 ++ I-50 + I-51 +++ I-52 +++ I-53 + I-54 + I-55 ++ I-56 ++I-57 ++ I-58 ++ EG4 + I-59 ++ I-60 ++ I-61 +++ I-62 ++ I-63 ++ I-64 +I-65 ++ I-66 + I-67 + I-68 + I-69 + I-70 + I-71 + I-72 ++ I-73 ++ I-74++ I-75 ++ I-76 + I-77 ++ I-78 ++ I-79 + I-80 + I-81 ++ I-82 ++ I-83 +++I-84 +++ I-85 + I-86 + I-87 + I-88 + I-89 + I-90 ++ I-91 ++ I-92 + I-93++ I-94 ++ I-95 ++ I-96 ++ I-97 ++ I-99 +++ I-100 +++ EG5 + I-101 +++I-102 +++ I-104 + I-105 ++ I-106 ++ I-107 ++ I-108 ++ I-109 ++ I-110 ++I-111 +++ I-98 ++ I-112 +++ I-113 + I-114 ++ I-115 ++ I-116 ++ I-117 +I-118 + I-119 ++ I-120 ++ I-121 +++ I-122 +++ I-123 ++ I-124 +++ I-125+++ I-126 +++ I-127 +++ I-128 ++ I-130 +++ I-131 +++ I-132 ++ I-133 +++I-134 +++ I-135 ++ I-136 +++ I-137 +++ I-138 +++ I-139 +++ I-140 +++I-141 +++ I-142 +++ I-143 +++ I-144 +++ I-145 +++ I-146 +++ I-147 +++I-148 ++ I-149 +++ I-150 +++ I-151 +++ I-152 +++ I-153 +++ I-154 ++I-155 +++ I-156 NT I-157 +++ I-158 +++ I-159 +++ I-160 +++ I-161 +++I-162 +++ I-163 +++ I-164 ++ I-165 ++ I-166 +++ I-167 +++ I-168 +++I-169 +++ I-170 +++ I-171 ++ I-172 ++ I-173 +++ I-174 +++ I-175 +++I-176 +++ I-177 +++ I-178 ++ I-179 +++ I-180 +++ I-181 ++ I-182 ++ I-183+++ I-184 +++ I-185 +++ I-186 +++ I-187 +++ I-188 +++ I-189 +++ I-190+++ I-191 ++ I-192 +++ I-193 +++ I-194 ++ I-195 ++ I-196 +++ I-197 ++I-198 ++ I-199 ++ I-200 +++ I-201 +++ I-202 +++ I-203 +++ I-204 ++ I-205+++ I-206 +++ I-207 +++ I-208 +++ I-209 ++ I-210 +++ I-211 +++ I-212 +++I-213 +++ IA-12 ++ IA-13 ++ I-214 ++ I-215 +++ I-216 +++ I-217 +++ I-218+++ I-219 +++ I-220 +++ I-221 ++ I-222 +++ IA-14 + I-223 ++ I-224 +++I-225 +++ I-226 +++ I-227 +++ I-228 +++ I-229 +++ I-230 +++ I-231 +++I-232 NT I-233 +++ I-234 +++ I-235 + I-236 +++ I-237 +++ I-238 +++ I-239+++ I-240 +++ I-241 ++ I-242 +++ I-243 +++ I-244 +++ I-245 + I-246 +++I-247 +++ I-248 ++ I-249 +++ I-250 +++ I-251 +++ I-252 ++ I-253 +++I-254 +++ I-255 +++ I-256 +++ I-257 +++ I-258 +++ I-259 +++ I-260 +++I-261 +++ I-262 +++ I-263 +++ I-264 +++ I-265 +++ I-266 +++ I-267 +++I-268 +++ I-269 ++ I-270 +++ I-271 ++ I-272 +++ I-273 +++ I-274 +++I-275 +++ I-276 +++ I-277 +++ I-278 +++ I-279 ++ I-280 ++ I-281 +++I-282 +++ I-283 ++ I-284 +++ I-285 +++ I-286 ++ I-287 ++ I-288 ++ I-289+++ I-290 ++ I-291 +++ I-292 +++ I-293 +++ I-294 ++ I-295 +++ I-296 +++I-297 +++ I-298 +++ I-299 +++ IA-2 + IA-3 ++ IA-4 ++ IA-5 ++ IA-6 +IA-7 + IA-8 + EG6 ++ EG7 ++ EG8 ++ IA-10 + IA-11 ++ I-300 +++ I-301 +I-302 +++ I-303 +++ I-304 NT

PLK2 Inhibition Assay:

Compounds were screened for their ability to inhibit PLK2 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, 0.1% BSA, and 2 mM DTT.Final substrate concentrations were 200 μM [γ-33P]ATP (57 mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μMpeptide (KKKISDELMDATFADQEAK) [SEQ ID:3]. Assays were carried out at 25°C. in the presence of 25 nM PLK2. An assay stock buffer solution wasprepared containing all of the reagents listed above, with the exceptionof ATP and the test compound of interest. 30 μL of the stock solutionwas placed in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 200 μM).

The reaction was stopped after 90 minutes by the addition of 100 μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate(Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.2Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK3 Inhibition Assay:

Compounds were screened for their ability to inhibit PLK3 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, and 1 mM DTT. Finalsubstrate concentrations were 75 μM [γ-33P]ATP (60 mCi 33P ATP/mmol ATP,Amersham Pharmacia Biotech/Sigma Chemicals) and 10 μM peptide (SAM68protein Δ332-443). Assays were carried out at 25° C. in the presence of5 nM PLK3 (S38-A340). An assay stock buffer solution was preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution wasplaced in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 75 μM).

The reaction was stopped after 60 minutes by the addition of 100 μL0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-wellplate (Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.2Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK4 Inhibition Assay:

Compounds are screened for their ability to inhibit PLK4 using aradioactive-phosphate incorporation assay. Assays are carried out in amixture of 8 mM MOPS (pH 7.5), 10 mM MgCl₂, 0.1% BSA and 2 mM DTT. Finalsubstrate concentrations are 15 μM [γ-33P]ATP (227 mCi 33P ATP/mmol ATP,Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μM peptide(KKKMDATFADQ) [SEQ ID:4]. Assays are carried out at 25° C. in thepresence of 25 nM PLK4. An assay stock buffer solution is preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution is placedin a 96 well plate followed by addition of 2 μL of DMSO stock containingserial dilutions of the test compound (typically starting from a finalconcentration of 10 μM with 2-fold serial dilutions) in duplicate (finalDMSO concentration 5%). The plate is pre-incubated for 10 minutes at 25°C. and the reaction initiated by addition of 8 μL [γ-33P]ATP (finalconcentration 15 μM).

The reaction is stopped after 180 minutes by the addition of 100 μL0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-wellplate (Millipore, Cat No. MAPHN0B50) is pretreated with 100 μL 0.2 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate is washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) is added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data are calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

Compounds of formula Id show selectivity for PLK1 over PLK2 and PLK3 asillustrated in the following table.

Ki_((PLK2)) Ki_((PLK3)) Compound No. Ki_((PLK1)) Ki_((PLK1)) I-102 11328 I-124 323 185 I-126 211 126 I-127 210 140 I-131 180 163 I-139 1000456 I-142 <30 <23 I-147 523 186 I-148 63 70 I-149 <130 <100 I-167 914586 I-267 1152 I-268 293 141 I-272 67 14 I-273 1813 581 I-274 4074 I-275313 919 I-276 2952 I-277 39 I-278 208 142

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1.-74. (canceled)
 75. A method of inhibiting PLK protein kinase activityin a patient or in a biological sample, comprising administering to saidpatient a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R¹ is —H,halogen, C₁₋₆ aliphatic optionally substituted with 1-3 R³, —O(C₁₋₆aliphatic) optionally substituted with 1-3 R³, or —N(H)R; Each R isindependently H, C₁₋₆ aliphatic, aryl, heteroaryl, C₃₋₈ cycloalkyl, or4-12 membered heterocyclic ring optionally containing 1-3 groupsselected from —N(R₁₇)—, —O—, or —S—; wherein each of the aliphatic,aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionallysubstituted with 1-3 of Q; Each Q is independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, benzyl, oxo, —CF₃, W, —CN, —NH₂, —N(H)—W,—N(W)₂, —N(H)—SO₂—W, —S(O)₂—N(H)—W, —S(O)₂—N(W)₂, —C(O)—W, —C(O)—N(W)₂,—N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, —SO₂—W, SW or —OW; Two Q can belinked together to form a 4- to 8-membered carbocyclic or heterocyclicring optionally substituted with C₁₋₃ alkyl or CF₃; Each W isindependently selected from —H, C₁₋₆ alkyl, aralkyl, cycloalkyl orheterocyclic ring; each C₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclicring is optionally substituted with 1-3 of halogen, —OR⁶, —CN, C₁₋₆alkyl or NR¹⁸R¹⁹; or One W, together with the nitrogen atom to which itis attached and a carbon atom of R, form a 4- to 8-membered ring; or TwoW, together with the same or different nitrogen atom or carbon atom towhich they are attached, form a 4- to 8-membered heterocyclic ring; EachR¹⁸ and R¹⁹ is independently hydrogen or C₁₋₃ alkyl; or R¹⁸ and R¹⁹,together with the nitrogen atom to which they are attached, form a 4- to8-membered heterocyclic ring, optionally substituted with C₁₋₃ alkyl orCF₃; Two W can be linked together to form a 4- to 8-membered cycloalkylor heterocycloalkyl optionally substituted with C₁₋₃ alkyl or CF₃; R² is—NR⁴R⁵, —OR⁶, —SR⁶, or —NR¹⁰R¹¹; Each R³ is independently halogen, C₁₋₆alkyl, aryl, or heteroaryl; Each R⁴ is independently —H or C₁₋₆aliphatic optionally substituted with 1-3 R⁷; Each R⁵ is independentlyC₁₋₆ aliphatic optionally substituted with 1-4 R⁷ or a 4- to 8-memberedmonocyclic or 6- to 10-membered bicyclic ring optionally substitutedwith 1-4 R⁷, or R⁴ and R⁵ can be joined together to form a monocyclic orbicyclic ring optionally substituted with 1-3 R⁹; Each R⁶ isindependently H, C₁₋₆ alkyl, -L-aryl, or -L-heteroaryl, wherein each ofthe C₁₋₆ alkyl, -L-aryl, or -L-heteroaryl is optionally andindependently substituted with 1-3 R⁸; L is C₀₋₃ alkyl; Each R⁷ isindependently oxo, alkyl, halogen, —CN, —OR⁹, —SR⁹, —N(R⁹)₂, C₃₋₈cycloalkyl, aryl, heteroaryl or a 4- to 8-membered heterocyclic ringcontaining 1-3 groups selected from —N(R¹⁷)—, —O—, or —S—, wherein eachalkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclicring, aryl, and heteroaryl is optionally and independently substitutedwith 1-3 R⁸, or Two R⁷ on the same atom or adjacent atoms is joined toform a carbocyclic ring or a 4- to 8-membered heterocyclic ringcontaining 1-3 groups selected from —N(R¹⁷)—, —O—, or —S—, wherein eachof the carbocyclic ring and the 4- to 8-membered heterocyclic ring isoptionally and independently substituted with 1-3 R⁸; Each R⁸ isindependently —R, -Q, —R⁹, —OR⁹, —N(R⁹)₂, halogen, or —CN; Each R⁹ isindependently —H, —N(R¹⁶)₂, C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclicring, or C₁₋₃ aliphatic, wherein C₃₋₆ carbocyclic ring, C₃₋₆heterocyclic ring and C₁₋₃ aliphatic are each optionally substitutedwith 1-3 Q; or Two R⁹ groups together with the N atom to which they arebound form a 4-8 membered ring additionally containing 1 or 2 groupseach independently selected from —N(R¹⁷)—, —O—, or —S—, wherein the 4-to 8-membered ring is optionally and independently substituted with 1-3of W; Each R¹⁶ is independently hydrogen or C₁₋₆ alkyl, or Two R¹⁶groups together with the N atom to which they are bound form a 4- to8-membered ring containing 1 or 2 groups selected from NR¹⁷, O, or S;Each R¹⁷ is independently, hydrogen, Q₁ or C₁₋₄ aliphatic orcycloaliphatic, wherein each C₁₋₄ aliphatic or cycloaliphatic isoptionally substituted with 1-3 of Q; Q₁ is C₁₋₆ alkyl, benzyl, —SO₂—W,—S(O)₂—N(H)—W, —S(O)₂—N(W)₂, —C(O)—W, —C(O)—N(W)₂—C(O)—N(H)—W,—N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, or —SO₂—W; R¹⁰ is —H or C₁₋₆aliphatic optionally substituted with 1-3 of R⁷; R¹¹ is—C(R¹²R¹³)C(═O)NR¹⁴R¹⁵; Each of R¹² and R¹³ is independently H or C₁₋₆aliphatic optionally substituted with 1-3 R⁷; or R¹² and R¹³ can bejoined together to form a ring optionally substituted with 1-3 of R⁹; orR¹⁰ and R¹² can be joined together to form a ring optionally substitutedwith 1-3 of R⁹; and Each R¹⁴ and R¹⁵ is independently H, C₁₋₆ alkyl,carbocyclic, or heterocyclic optionally substituted with 1-3 of R⁷; orR¹⁴ and R¹⁵ can be joined together to form a ring optionally substitutedwith 1-3 of R⁹. 76.-80. (canceled)
 81. A method of treating solid tumor,melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancerselected from colon, breast, gastric, ovarian, cervical, lung, centralnervous system (CNS), renal, prostate, bladder, pancreatic, orurogenital cancer, lung cancer, gastrointestinal cancer, head and neckcancer, malignant mesothelioma, breast cancer, malignant melanoma,childhood cancer and bone or soft tissue sarcoma, in a patient whereinsaid method comprises administering to said patient a compoundrepresented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R¹ is —H,halogen, C₁₋₆ aliphatic optionally substituted with 1-3 R³, —O(C₁₋₆aliphatic) optionally substituted with 1-3 R³, or —N(H)R; Each R isindependently H, C₁₋₆ aliphatic, aryl, heteroaryl, C₃₋₈ cycloalkyl, or4-12 membered heterocyclic ring optionally containing 1-3 groupsselected from —N(R₁₇)—, —O—, or —S—; wherein each of the aliphatic,aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionallysubstituted with 1-3 of Q; Each Q is independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, benzyl, oxo, —CF₃, W, —CN, —NH₂, —N(H)—W,—N(W)₂, —N(H)—SO₂—W, —S(O)₂—N(H)—W, —S(O)₂—N(W)₂, —C(O)—W, —C(O)—N(W)₂,—N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, —SO₂—W, SW or —OW; Two Q can belinked together to form a 4- to 8-membered carbocyclic or heterocyclicring optionally substituted with C₁₋₃ alkyl or CF₃; Each W isindependently selected from —H, C₁₋₆ alkyl, aralkyl, cycloalkyl orheterocyclic ring; each C₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclicring is optionally substituted with 1-3 of halogen, —OR⁶, —CN, C₁₋₆alkyl or NR¹⁸R¹⁹; or One W, together with the nitrogen atom to which itis attached and a carbon atom of R, form a 4- to 8-membered ring; or TwoW, together with the same or different nitrogen atom or carbon atom towhich they are attached, form a 4- to 8-membered heterocyclic ring; EachR¹⁸ and R¹⁹ is independently hydrogen or C₁₋₃ alkyl; or R¹⁸ and R¹⁹,together with the nitrogen atom to which they are attached, form a 4- to8-membered heterocyclic ring, optionally substituted with C₁₋₃ alkyl orCF₃; Two W can be linked together to form a 4- to 8-membered cycloalkylor heterocycloalkyl optionally substituted with C₁₋₃ alkyl or CF₃; R² is—NR⁴R⁵, —OR⁶, —SR⁶, or —NR¹⁰R¹¹; Each R³ is independently halogen, C₁₋₆alkyl, aryl, or heteroaryl; Each R⁴ is independently —H or C₁₋₆aliphatic optionally substituted with 1-3 R⁷; Each R⁵ is independentlyC₁₋₆ aliphatic optionally substituted with 1-4 R⁷ or a 4- to 8-memberedmonocyclic or 6- to 10-membered bicyclic ring optionally substitutedwith 1-4 R⁷, or R⁴ and R⁵ can be joined together to form a monocyclic orbicyclic ring optionally substituted with 1-3 R⁹; Each R⁶ isindependently H, C₁₋₆ alkyl, -L-aryl, or -L-heteroaryl, wherein each ofthe C₁₋₆ alkyl, -L-aryl, or -L-heteroaryl is optionally andindependently substituted with 1-3 R⁸; L is C₀₋₃ alkyl; Each R⁷ isindependently oxo, alkyl, halogen, —CN, —OR⁹, —SR⁹, —N(R⁹)₂, C₃₋₈cycloalkyl, aryl, heteroaryl or a 4- to 8-membered heterocyclic ringcontaining 1-3 groups selected from —N(R¹²)—, —O—, or —S—, wherein eachalkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclicring, aryl, and heteroaryl is optionally and independently substitutedwith 1-3 R⁸, or Two R⁷ on the same atom or adjacent atoms is joined toform a carbocyclic ring or a 4- to 8-membered heterocyclic ringcontaining 1-3 groups selected from —N(R¹⁷)—, —O—, or —S—, wherein eachof the carbocyclic ring and the 4- to 8-membered heterocyclic ring isoptionally and independently substituted with 1-3 R⁸; Each R⁸ isindependently —R, -Q, —R⁹, —OR⁹, —N(R⁹)₇, halogen, or —CN; Each R⁹ isindependently —H, —N(R¹⁶)₂, C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclicring, or C₁₋₃ aliphatic, wherein C₃₋₆ carbocyclic ring, C₃₋₆heterocyclic ring and C₁₋₃ aliphatic are each optionally substitutedwith 1-3 Q; or Two R⁹ groups together with the N atom to which they arebound form a 4-8 membered ring additionally containing 1 or 2 groupseach independently selected from —N(R¹⁷)—, —O—, or —S—, wherein the 4-to 8-membered ring is optionally and independently substituted with 1-3of W; Each R¹⁶ is independently hydrogen or C₁₋₆ alkyl, or Two R¹⁶groups together with the N atom to which they are bound form a 4- to8-membered ring containing 1 or 2 groups selected from NR¹², O, or S;Each R¹⁷ is independently, hydrogen, Q₁ or C₁₋₄ aliphatic orcycloaliphatic, wherein each C₁₋₄ aliphatic or cycloaliphatic isoptionally substituted with 1-3 of Q; Q₁ is C₁₋₆ alkyl, benzyl, —SO₂—W,—S(O)₂—N(H)—W, —S(O)₂—N(W)₂, —C(O)—W, —C(O)—N(W)₂, —C(O)—N(H)—W,—N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, or —SO₂—W; R¹⁰ is —H or C₁₋₆aliphatic optionally substituted with 1-3 of R⁷; R¹¹ is—C(R¹²R¹³)C(═O)NR¹⁴R¹⁵; Each of R¹² and R¹³ is independently H or C₁₋₆aliphatic optionally substituted with 1-3 R⁷; or R¹² and R¹³ can bejoined together to form a ring optionally substituted with 1-3 of R⁹; orR¹⁰ and R¹² can be joined together to form a ring optionally substitutedwith 1-3 of R⁹; and Each R¹⁴ and R¹⁵ is independently H, C₁₋₆ alkyl,carbocyclic, or heterocyclic optionally substituted with 1-3 of R⁷; orR¹⁴ and R¹⁵ can be joined together to form a ring optionally substitutedwith 1-3 of R⁹. 82.-91. (canceled)
 92. The method of claim 80, whereinR¹ is halogen.
 93. The method of claim 80, wherein R¹ is methyloptionally substituted with 1-3 R³ and each R³ is independently halo.94. The c method of claim 93, wherein R¹ is —CF₃.
 95. The method ofclaim 93, wherein R¹ is —NHR and R is H, C₁₋₆ aliphatic, aryl, or C₃₋₈cycloalkyl.
 96. The method of claim 95, wherein R is H, C₁₋₆ alkyl, oraryl.
 97. The method of claim 95, wherein R² is —NR⁴R⁵, wherein R⁴ is Hor C₁₋₆ aliphatic optionally substituted with 1-3 R⁷, and R⁵ is C₁₋₆aliphatic optionally substituted with 1-4 R⁷ or a 3- to 6-memberedmonocyclic or 6- to 10-membered bicyclic ring optionally substitutedwith 1-4 R⁷.
 98. The method of claim 97, wherein R⁴ is H, and R⁵ is C₁₋₄alkyl and optionally substituted with 1-4 R⁷.
 99. The method of claim98, wherein R⁵ is ethyl substituted at the carbon atom attached to thenitrogen atom with R⁷.
 100. The method of claim 99, wherein R⁷ isphenyl, pyridyl, or pyrimidyl, and is optionally substituted with 1-3 ofR⁸.
 101. The method of claim 97, wherein R⁷ is phenyl substituted at thepara-position with —R or —N(R⁹)₂; R is 4- to 8-membered heterocyclicring optionally containing 1-3 groups each independently selected from—N(R¹⁷)—, —O—, or —S—, and the heterocyclic ring is optionallysubstituted with 1-3 of Q; Each Q is independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, benzyl, —CF₃, W, —C(O)—W, —C(O)—N(W)₂,—C(O)—O—W; Each W is independently selected from —H, C₁₋₆ alkyl, orcycloalkyl; Each R⁹ is independently —H, C₃₋₆ heterocyclic ring, or C₁₋₃aliphatic, wherein C₃₋₆ heterocyclic ring and C₁₋₃ aliphatic are eachoptionally substituted with 1-3 Q; or Two R⁹ groups together with the Natom to which they are bound form a 4- to 8-membered ring containingadditional 1 or 2 groups each independently selected from —N(R¹⁷)—, —O—,or —S—, wherein the 4- to 8-membered ring is optionally andindependently substituted with 1-3 of W.
 102. The method of claim 97,wherein R⁷ is


103. The method of claim 97, wherein R⁷ is pyrimidinyl optionallysubstituted with 1-3 of R⁸, 5-pyrimidyl optionally substituted at the2-position with R⁸, or pyridinyl optionally substituted with 1-3 of R⁸.104. The method of claim 103, wherein R⁷ is


105. The method of claim 100, wherein one R⁸ is aryl, heteroaryl, C₃-C₈cycloalkyl, or 4- to 8-membered heterocyclic ring each optionallysubstituted with 1-3 of Q.
 106. The method of claim 100, wherein one R⁸is Q, and wherein Q is —NHW, —NW₂, —NH—SO₂W, —NH—COW, —CO—NHW, —CO—NW₂,—SO₂NHW, —SO₂—NW₂, —SW, —OW, or —W.
 107. The method of claim 106,wherein W is C₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclic ring; eachC₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionallysubstituted with 1-3 of halogen, —OR⁶, —CN, C₁₋₆ alkyl, C₁₋₆ alkyl or—NR¹⁸R¹⁹.
 108. The method of claim 107, wherein W is C₁₋₆ alkyl orheterocyclic ring; each C₁₋₆ alkyl, aralkyl, cycloalkyl or heterocyclicring is optionally substituted with 1-3 of halogen, —OR⁶, —CN, C₁₋₆alkyl, C₁₋₆ alkyl or —NR¹⁸R¹⁹.
 109. The method of claim 100, wherein oneR⁸ is —R⁹, —OR⁹ or —N(R⁹)₂.
 110. The method of claim 109, wherein R⁹ isindependently H, C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclic ring, or C₁₋₃aliphatic, wherein C₃₋₆ carbocyclic ring, C₃₋₆ heterocyclic ring andC₁₋₃ aliphatic are each optionally substituted with 1-3 Q; or Two R⁹groups, together with the N atom to which they are bound, form a 4- to8-membered ring optionally containing additional 1 or 2 groups selectedfrom —N(R¹⁷)—, —O—, or —S—, wherein the 4- to 8-membered ring isoptionally and independently substituted with 1-3 of W.
 111. The methodof claim 97, wherein R⁷ is a 4- to 10-membered heterocyclic monocyclicor bicyclic ring optionally substituted with 1-3 of R⁸.
 112. The methodof claim 111, wherein R⁷ is a 4- to 6-membered heterocyclic monocyclicring optionally substituted with 1-3 of R⁸.
 113. The method of claim112, wherein R⁸ is Q selected from —C(O)—W, —C(O)—N(W)₂—C(O)—O—W or—SO₂—W.
 114. The method of claim 111, wherein R⁷ is a C₃-C₈ carbocycleoptionally substituted with 1-3 R⁸.
 115. The method of claim 114,wherein one R⁸ is Q selected from hydroxy, —NH₂, —N(H)—W, |—N(W)₂,—N(H)—SO₂—W, —C(O)—N(W)₂, —N(H)—C(O)—W, or —O—C(O)—W.
 116. The method ofclaim 95, wherein R² is —NR¹⁰R¹¹.
 117. The method of claim 116, whereinR¹⁰ is —H and R¹¹ is —C(R¹²R¹³)C(═O)NR¹⁴R¹⁵, wherein R¹² is H; R¹³ isC₁₋₃ alkyl; R¹⁴ is H; and R¹⁵ is alkyl substituted with trifluoromethylor hydroxy, or R¹⁵ is cycloalkyl substituted with hydroxy.
 118. Themethod of claim 95, wherein R² is −OR⁶ or —SR⁶; and R⁶ is optionallysubstituted phenyl.
 119. The method of claim 1, selected from compoundsI-1 through I-304 or a pharmaceutically acceptable salt thereof:


120. The method of claim 1, selected from compounds IA-0 through IA-13or a pharmaceutically acceptable salt thereof:


121. The method of claim 1, selected from compounds II-0 through II-17or a pharmaceutically acceptable salt thereof: